Fused pyrrolocarbazoles

ABSTRACT

The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. Provisional Application No.60/532,182, filed Dec. 23, 2003, which is incorporated herein byreference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates generally to fused pyrrolocarbazoles,including pharmaceutical compositions, diagnostic kits, assay standardsor reagents containing the same, and methods of using the same astherapeutics. The invention is also directed to intermediates andprocesses for making these novel compounds.

BACKGROUND OF THE INVENTION

Publications cited throughout this disclosure are incorporated in theirentirety herein by reference.

Various synthetic small organic molecules that are biologically activeand generally known in the art as “fused pyrrolocarbazoles” have beenprepared (See U.S. Pat. Nos. 5,475,110; 5,591,855; 5,594,009; 5,616,724;and 6,630,500). In addition, U.S. Pat. No. 5,705,511 discloses fusedpyrrolocarbazole compounds which possess a variety of functionalpharmacological activities. The fused pyrrolocarbazoles were disclosedto be used in a variety of ways, including: enhancing the functionand/or survival of cells of neuronal lineage, either singularly or incombination with neurotrophic factor(s) and/or indolocarbazoles;enhancing trophic factor-induced activity; inhibition of protein kinaseC (“PKC”) activity; inhibition of trk tyrosine kinase activity;inhibition of proliferation of a prostate cancer cell-line; inhibitionof the cellular pathways involved in the inflammation process; andenhancement of the survival of neuronal cells at risk of dying. However,there remains a need for novel pyrrolocarbazole derivatives that possessbeneficial properties. This invention is directed to this, as well asother important ends.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to fusedpyrrolocarbazole compounds of Formula I:

and its stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt forms thereof, wherein the constituentmembers are defined infra.

The fused pyrrolocarbazoles of the present invention may be used in avariety of ways, including: for inhibition of angiogenesis; as antitumoragents; for enhancing the function and/or survival of cells of neuronallineage, either singularly or in combination with neurotrophic factor(s)and/or indolocarbazoles; for enhancing trophic factor-induced activity;inhibition of kinase activity, such as trk tyrosine kinase (“trk”),vascular endothelial growth factor receptor (“VEGFR”) kinase, preferablyVEGFR1 and VEGFR2, mixed lineage kinase (“MLK”), dual leucine zipperbearing kinase (“DLK”), platelet derived growth factor receptor kinase(“PDGFR”), protein kinase C (“PKC”), Tie-2, or CDK-1, -2, -3, -4, -5,-6; for inhibition of NGF-stimulated trk phosphorylation; for inhibitionof proliferation of a prostate cancer cell-line; for inhibition of thecellular pathways involved in the inflammation process; and forenhancement of the survival of neuronal cells at risk of dying. Inaddition, the fused pyrrolocarbazoles may useful for inhibition ofc-met, c-kit, and mutated Flt-3 containing internal tandem duplicationsin the juxtamembrane domain. Because of these varied activities, thedisclosed compounds find utility in a variety of settings, includingresearch and therapeutic environments.

In other embodiments, the compounds of the present invention are usefulfor treating or preventing angiogenesis and angiogenic disorders such ascancer of solid tumors, endometriosis, retinopathy, diabeticretinopathy, psoriasis, hemangioblastoma, ocular disorders or maculardegeneration. In another embodiment, the compounds of the presentinvention are useful for treating or preventing neoplasia, rheumatoidarthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis,abnormal wound healing, atherosclerosis, or restenosis. In furtherembodiments, the compounds of the present invention are useful fortreating or preventing neurodegenerative diseases and disorders, such asAlzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease,stroke, ischemia, Huntington's disease, AIDS dementia, epilepsy,multiple sclerosis, peripheral neuropathy, chemotherapy inducedperipheral neuropathy, AIDS related peripheral neuropathy, or injuriesof the brain or spinal chord. In additional embodiments, the compoundsof the present invention are useful for treating or preventing prostatedisorders such as prostate cancer or benign prostate hyperplasia. Instill other embodiments, the compounds of the present invention areuseful for treating or preventing multiple myeloma and leukemiasincluding, but not limited to, acute myelogenous leukemia, chronicmyelogenous leukemia, acute lymphocytic leukemia, and chroniclymphocytic leukemia.

In further aspect, the present invention is directed to pharmaceuticalcompositions which comprises one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of a compound of thepresent invention.

DETAILED DESCRIPTION

Thus, in a first embodiment, the present invention provides a novelcompound of Formula I:

wherein:

-   -   ring A and ring B, independently, and each together with the        carbon atoms to which they are attached, are selected from:        -   (a) a phenylene ring in which from 1 to 3 carbon atoms may            be replaced by nitrogen atoms; and        -   (b) a 5-membered aromatic ring in which either            -   (1) one carbon atom may be replaced with an oxygen,                nitrogen, or sulfur atom;            -   (2) two carbon atoms may be replaced with a sulfur and a                nitrogen atom, an oxygen and a nitrogen atom, or two                nitrogen atoms; or            -   (3) three carbon atoms may be replaced with three                nitrogen atoms, one oxygen and two nitrogen atoms, or                one sulfur and two nitrogen atoms;    -   A¹ and A² are independently selected from H, H; H, OR; H, SR; H,        N(R)₂; and a group wherein A¹ and A² together form a moiety        selected from ═O, ═S, and ═NR;    -   B¹ and B² are independently selected from H, H; H, OR; H, SR; H,        N(R)₂; and a group wherein B¹ and B² together form a moiety        selected from ═O, ═S, and ═NR;    -   provided that at least one of the pairs A¹ and A², or B¹ and B²        forms ═O;    -   R is independently selected from H, optionally substituted        alkyl, C(═O)R^(1a), C(═O)NR^(1c)R^(1d), optionally substituted        arylalkyl and optionally substituted heteroarylalkyl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R¹ is independently selected from H, C(═O)R^(1a), OR^(1b),        C(═O)NHR^(1b), NR^(1c)R^(1d), and optionally substituted alkyl,        wherein said optional substituents are one to three R¹⁰ groups;    -   R^(1a) is independently selected from optionally substituted        alkyl, optionally substituted aryl and optionally substituted        heteroaryl, wherein said optional substituents are one to three        R¹⁰ groups;    -   R^(1b) is independently selected from H and optionally        substituted alkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R^(1c) and R^(1d) are each independently selected from H and an        optionally substituted alkyl, or together with the nitrogen to        which they are attached form an optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R² is selected from H, C(═O)R^(2a), C(═O)NR^(2c)R^(2d),        SO₂R^(2b), CO₂R^(2b), (alkylene)-OC(═O)-(alkylene)CO₂R¹¹,        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        cycloalkyl, and optionally substituted heterocycloalkyl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R^(2a) is independently selected from optionally substituted        alkyl, optionally substituted aryl, OR^(2b), and NR^(2c)R^(2d),        wherein said optional substituents are one to three R¹⁰ groups;    -   R^(2b) is selected from H and optionally substituted alkyl,        wherein said optional substituents are one to three R¹⁰ groups;    -   R^(2c) and R^(2d) are each independently selected from H and        optionally substituted alkyl, or together with the nitrogen to        which they are attached form an optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   at least one of R³, R⁴, R⁵, and R⁶ is selected from        (alkylene)_(x)OR¹³, C(═O)R¹³, (CH₂)_(p)OR²², O-(alkylene)-R²⁷,        OCH(CO₂R¹⁸)₂, OCH[(CH₂)_(p)OR²⁰]₂, C(═O)-(alkylene)-R²⁵,        NR¹¹R³², NR¹¹R³³, (alkylene)-NR¹⁸R¹⁹, C(R¹²)═N—R¹⁸, CH═N—OR¹³,        C(R¹²)═N—OR²⁰, C(R¹¹)═N—NR¹¹C(═O)NR^(14A)R^(14B),        C(R¹¹)═N—NR¹¹SO₂R¹⁸, OC(═O)NR¹¹(alkylene)-R²⁶,        OC(═O)[N(CH₂CH₂)₂N]—R²¹, NR¹¹C(═O)OR²³, NR¹¹C(═O)S—R¹⁸,        NR¹¹C(═O)NR¹¹R²³, NR¹¹C(═S)NR¹¹R²³, NR¹¹S(═O)₂N(R¹⁵)₂,        NR¹¹C(═O)NR¹¹(alkylene)-R²⁴, NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B),        substituted alkyl, wherein one of the substituents is a        spirocycloalkyl group, optionally substituted        (alkylene)_(x)-cycloalkyl, and optionally substituted        -(alkylene)_(x)-heterocycloalkyl, wherein the heterocycloalkyl        does not include unsubstituted N-morpholinyl, N-piperidyl, or        N-thiomorpholinyl,        -   wherein any said alkylene group may be optionally            substituted with one to three R¹⁰ groups;        -   provided that when R³, R⁴, R⁵, or R⁶ is C(═O)R¹³, then R¹³            does not include a heterocycloalkyl group that contains a            nitrogen bonded to the carbonyl moiety; and    -   the other R³, R⁴, R⁵, or R⁶ moieties can be selected        independently from H, halogen, R¹⁰, OR²⁰, optionally substituted        alkyl, optionally substituted alkenyl, and optionally        substituted alkynyl, wherein said optional substituents are one        to three R¹⁰ groups;    -   Q is selected from an optionally substituted C₁₋₂ alkylene,        wherein said optional substituents are one to three R¹⁰ groups,        CR²⁰═CR²⁰, O, S(O)_(y), C(R⁷)═N, N═C(R⁷), CH₂—Z′, and Z′—CH₂;        wherein        -   Z′ is selected from O, S, C═O, and C(═NOR¹¹);    -   R⁷ is selected from H, optionally substituted alkyl, and OR¹¹,        wherein said optional substituents are one to three R¹⁰ groups;    -   R¹⁰ is selected from alkyl, aryl, heteroaryl, cycloalkyl,        spirocycloalkyl, heterocycloalkyl, arylalkoxy, F, Cl, Br, I, CN,        CF₃, NR^(31A)R^(31B), NO₂, OR³⁰, OCF₃, ═O, ═NR³⁰, ═N—OR³⁰,        ═N—NR^(31A)R^(31B), OC(═O)R³⁰, OC(═O)NHR²⁹, O—Si(R²⁹)₄,        O-tetrahydropyranyl, ethylene oxide, NR²⁹C(═O)R³⁰, NR²⁹CO₂R³⁰,        NR²⁹C(═O)NR^(31A)R^(31B), NHC(═NH)NH₂, NR²⁹S(O)₂R³⁰,        S(O)_(y)R¹⁸, CO₂R³⁰, C(═O)NR^(31A)R^(31B), C(═O)R³⁰,        (CH₂)_(p)OR³⁰, CH═NNR^(31A)R^(31B), CH═NOR³⁰, CH═NR³⁰,        CH═NNHCH(N═NH)NH₂, S(═O)₂NR^(31A)R^(31B), P(═O)(OR³⁰)₂, OR²⁸,        and a monosaccharide wherein each hydroxyl group of the        monosaccharide is independently either unsubstituted or is        replaced by H, alkyl, alkylcarbonyloxy, or alkoxy;    -   R¹¹ is selected from H and optionally substituted alkyl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R¹² is selected from optionally substituted alkyl, optionally        substituted aryl, and optionally substituted heteroaryl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R¹³ is independently selected from optionally substituted        cycloalkyl, and optionally substituted heterocycloalkyl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R^(14A) and R^(14B) are each independently selected from H,        optionally substituted alkyl, optionally substituted aryl, and        optionally substituted heteroaryl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R¹⁵ is independently selected from optionally substituted alkyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted cycloalkyl, and optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R^(16A) and R^(16B) are each independently selected from H and        an optionally substituted alkyl, or together with the nitrogen        to which they are attached form an optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R¹⁷ selected from optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, and optionally substituted        heteroaryl, wherein said optional substituents are one to three        R¹⁰ groups;    -   R¹⁸ is selected from H, optionally substituted alkyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted cycloalkyl, and optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R¹⁹ is selected from CN and triazole;    -   R²⁰ is selected from H, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, optionally        substituted aryl, optionally substituted arylalkyl, optionally        substituted heteroaryl, optionally substituted cycloalkyl, and        optionally substituted heterocycloalkyl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R²¹ is selected from optionally substituted aryl, and optionally        substituted heteroaryl, wherein said optional substituents are        one to three R¹⁰ groups;    -   R²² is optionally substituted C₅–C₁₀ alkyl, wherein said        optional substituents are one to three R¹⁰ groups;    -   R²³ is selected from optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkyl, and        optionally substituted heterocycloalkyl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R²⁴ is selected from optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, OR²⁰, O(CH₂)_(p)OR²⁰,        (CH₂)_(p)OR²⁰, SR¹⁷, SOR¹⁵, SO₂R¹⁸, CN, N(R¹⁸)₂, C(═O)N(R¹⁸)₂,        NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸, C(R¹²)═NOR¹⁸,        NHOR²⁰, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸, OCOR¹⁵,        OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁵, and C(═O)R¹⁸, wherein said        optional substituents are one to three R¹⁰ groups;    -   R²⁵ is selected from optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, OR²⁰, O(CH)_(p)OR²⁰,        (CH₂)_(p)OR²⁰, SR¹⁷, SOR¹⁵, SO₂R¹⁸, CN, N(R¹⁷)₂, C(═O)N(R¹⁸)₂,        NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸, C(R¹²)═NOR¹⁸,        NHOR²⁰, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸, OCOR¹⁵,        OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁵, and C(═O)R¹⁸, wherein said        optional substituents are one to three R¹⁰ groups;    -   R²⁶ is selected from optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, OR¹¹, O(CH₂)_(p)OR²⁰,        (CH₂)_(p)OR²⁰, SR¹⁷, SOR¹⁵, SO₂R¹⁸, CN, N(R¹⁸)₂, C(═O)N(R¹⁸)₂,        NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸, C(R¹²)═NOR¹⁸,        NHOR²⁰, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸, OCOR¹⁵,        OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁵, and C(═O)R¹⁸, wherein said        optional substituents are one to three R¹⁰ groups;    -   R²⁷ is selected from optionally substituted cycloalkyl, CN,        C(R¹²)═NOR¹⁸, and C(═O)N(R¹⁸)₂, wherein said optional        substituents are one to three R¹⁰ groups;    -   R²⁸ is the residue of an amino acid after the removal of the        hydroxyl moeity from the carboxyl group thereof;    -   R²⁹ is H or alkyl;    -   R³⁰ is H, alkyl, aryl, arylalkyl, heteroaryl, cycloalkyl, or        heterocycloalkyl;    -   R^(31A) and R^(31B) are each independently selected from H,        alkyl, and arylalkyl, or together with the nitrogen to which        they are attached form a heterocycloalkyl;    -   R³² is optionally substituted aryl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R³³ is optionally substituted cycloalkyl, optionally substituted        heteroaryl, or optionally substituted heterocycloalkyl, wherein        said optional substituents are one to three R¹⁰ groups;    -   p is independently selected from 1, 2, 3, and 4;    -   x is 0 or 1;    -   y is independently selected from 0, 1 and 2; or    -   a stereoisomeric or pharmaceutically acceptable salt form        thereof.

In other embodiments, the compounds of Formula I as defined herein arenot intended to include any compounds disclosed in PCT Publ. No. WO02/28861. In particular, when R¹ is H; A¹, A² and B¹, B² are each ═O or═S; ring A is a phenylene, ring B is

wherein R^(A) is H or C₁–C₄ alkyl; and Q is CR²⁰═CR²⁰, wherein R²⁰ is H,C₁–C₄ alkyl or C₁–C₄ alkoxy; then neither R³ or R⁴ includes(alkylene)-NR^(a)R^(b), wherein R^(a) and R^(b) combine with thenitrogen to which they are attached to form a heterocycloalkyl group.

In another embodiment, the compounds of Formula I as defined herein arenot intended to include any compounds disclosed in PCT Publ. No. WO02/30942. In particular, when A¹, A² is ═O; B¹, B² are independently Hor OH, or B¹, B² combine to form ═O; rings A and B are each a phenylene;Q is O, S, or CH₂; and R² is H, or optionally substituted

then any of R³, R⁴, R⁵, and R⁶ cannot include (alkylene)_(x)OR¹³,wherein R¹³ is cycloalkyl; (CH₂)_(p)OR²², wherein R²² is C₅–C₇ alkyl;O-(alkylene)-R²⁷, wherein R²⁷ is CN; OCH[(CH₂)_(p)OR²⁰]₂; NR¹¹R³³,wherein R³³ is cycloalkyl; or NR^(a)R^(b), wherein R^(a) and R^(b)combine with the nitrogen to which they are attached to form aheterocycloalkyl group.

In a further embodiment, the compounds of Formula I as defined hereinare not intended to include any compounds disclosed in PCT Publ. No. WO02/28874. In particular, when A¹, A² and B¹, B² are each ═O; rings A andB are each a phenylene; Q is O or S; and R² is optionally substituted

then any of R³, R⁴, R⁵, and R⁶ cannot include (alkylene)_(x)OR¹³,wherein R¹³ is cycloalkyl; (CH₂)_(p)OR²², wherein R²² is C₅–C₇ alkyl;O-(alkylene)-R₂₇, wherein R²⁷ is CN; OCH[(CH₂)_(p)OR²⁰]₂; NR¹¹R³³,wherein R³³ is cycloalkyl; or NR^(a)R^(b), wherein R^(a) and R^(b)combine with the nitrogen to which they are attached to form aheterocycloalkyl group.

In an additional embodiment, the compounds of Formula I as definedherein are not intended to include any compounds disclosed in PCT Publ.No. WO 98/07433. In particular, when A¹, A² is ═O; B¹, B² areindependently H or OH, or B¹, B² combine to form ═O; rings A and B areeach a phenylene; Q is O, S, or CH—R^(a); and one of R² or R^(a) is Hand the other is optionally substituted

wherein W is optionally substituted C₁ alkyl, or NR^(31A)R^(31B); thenany of R³, R⁴, R⁵, and R⁶ cannot include OR¹³ or C(═O)NR^(c)R^(d)wherein R^(c) and R^(d) combine with the nitrogen to which they areattached to form a heterocycloalkyl group.

In a further embodiment, preferred compounds of Formula I as definedherein exclude certain compounds in which any of R³, R⁴, R⁵, and R⁶include (CH₂)_(p)OR²². In particular, in this embodiment, when R¹ is H;A¹, A² are both H; B¹, B² taken together are ═O; rings A and B are botha phenylene, wherein ring B is unsubstituted; R² is CH₂CH₂CH₂OH; and Qis CH₂, then R³ and R⁴ cannot include (CH₂)_(p)OR²².

Other aspects of the present invention include the compounds of FormulaI as defined herein wherein rings A and B are a phenylene; or one ofrings A and B are a phenylene, and the other ring A or ring B, togetherwith the carbon atoms to which they are attached, are selected from a5-membered aromatic ring in which one or two carbon atoms may bereplaced with a nitrogen atom, preferably a pyrazolylene, and morepreferably

Further aspects include those compounds wherein R¹ is selected from H,substituted alkyl, and unsubstituted alkyl. Another aspect includesthose compounds wherein R² is H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oroptionally substituted cycloalkyl, and preferably where R² is H oroptionally substituted alkyl. Additional aspects include those compoundswherein groups A¹, A² and B¹, B² are each independently selected from H,H; and a group wherein A¹, A² or B¹, B² together form ═O, and preferablythose wherein A¹A² are H, H; and B¹B² together form ═O. In yet anotheraspect, the invention includes compounds wherein Q is selected from anoptionally substituted C₁₋₂ alkylene, or preferably Q is CH₂ or CH₂CH₂.Additional aspects of the present invention include any combination ofthe above preferred substituents, such as, for example, a compound ofFormula I with the preferred moieties of groups R¹ and R²; or R¹ and Q;or R¹, R²; or Q; etc.

In another embodiment of the present invention, there are includedcompounds having a structure of Formula II:

wherein ring B together with the carbon atoms to which it is attached,is selected from:

-   -   (a) a phenylene ring in which from 1 to 3 carbon atoms may be        replaced by nitrogen atoms; and    -   (b) a 5-membered aromatic ring in which from 1 to 2 carbon atoms        may be replaced by nitrogen atoms.

In one aspect, there are included compounds of Formula II wherein the Bring is a phenylene, or ring B is a pyrazolylene, or preferably

Another aspect includes those compounds wherein R¹ is selected from H,substituted alkyl, and unsubstituted alkyl. Further aspects includethose compounds wherein R² is H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oroptionally substituted cycloalkyl, and preferably where R² is H oroptionally substituted alkyl. Additional aspects include those compoundswherein groups A¹, A² and B¹, B² are each independently selected from H,H; and a group wherein A¹, A² or B¹, B² together form ═O, and preferablythose wherein A¹A² are H, H; and B¹B² together form ═O. In yet anotheraspect, the invention includes compounds wherein Q is selected from anoptionally substituted C₁₋₂ alkylene, or preferably Q is CH₂ or CH₂CH₂.Additional aspects of the present invention include any combination ofthe above preferred substituents, such as, for example, a compound ofFormula II with the preferred moieties of groups R¹ and R²; or R¹ and Q;or R¹, R²; or Q; etc.

In yet another embodiment of the present invention, there are includedcompounds having a structure of Formula III:

where preferrably ring B is a phenylene, or ring B is a pyrazolylene,preferably

and where R¹ is selected from H and optionally substituted alkyl;and Formula IV:

and Formula V:

and Formula VI:

In certain aspects of the present invention, there are includedcompounds of Formulas III–VI wherein R² is H, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,or optionally substituted cycloalkyl, or preferably where R² is H oroptionally substituted alkyl. Other aspects include those compoundswherein Q is selected from an optionally substituted C₁₋₂ alkylene, orpreferably Q is CH₂ or CH₂CH₂. Additional aspects of the presentinvention include any combination of the above preferred substituentsfor each of Formulas III–VI.

The following paragraphs show additional aspects of the invention for atleast one R³, R⁴, R⁵, and R⁶ for compounds of Formulas I–VI and theirrespective preferred embodiments described heretofore.

-   -   1. OR¹³; especially those where R¹³ is optionally substituted        cycloalkyl, and particularly those where the cycloalkyl is a 5        or 6 membered ring.    -   2. C(═O)R¹³; especially those where R¹³ is optionally        substituted cycloalkyl, and particularly those where the        cycloalkyl is a 5 or 6 membered ring.    -   3. (alkylene)OR¹³; especially those where R¹³ is optionally        substituted cycloalkyl, and particularly those where the        cycloalkyl is a 5 or 6 membered ring.    -   4. (CH₂)_(p)OR²²; especially those where R²² is a branched chain        alkyl.    -   5. O-(alkylene)-R²⁷.    -   6. OCH(CO₂R¹⁸)₂; especially those where R¹⁸ is optionally        substituted alkyl.    -   7. OCH[(CH₂)_(p)OR²⁰]₂; especially those where R²⁰ is optionally        substituted alkyl.    -   9. C(═O)-(alkylene)-R²⁵.    -   9. NR¹¹R³³; especially those where R³³ is optionally substituted        heteroaryl.    -   10. (alkylene)-NR¹⁸R¹⁹; especially those where R¹⁸ is H or        optionally substituted alkyl.    -   11. C(R¹²)═N—R¹⁸; especially those where R¹² is alkyl, and those        where R¹⁸ is optionally substituted heterocycloalkyl.    -   12. CH═N—OR¹³; especially those where R¹³ is optionally        substituted heterocycloalkyl.    -   13. C(R¹²)═N—OR²⁰; especially those where R¹² and R³⁰ are        optionally substituted alkyl.    -   14. C(R¹¹)═N—NR¹¹C(═O)NR^(14A)R^(14B).    -   15. C(R¹¹)═N—NR¹¹SO₂R¹³.    -   16. OC(═O)NR¹¹(alkylene)-R²⁶; especially those where R²⁶ is        optionally substituted aryl or optionally substituted        heteroaryl.    -   17. OC(═O)[N(CH₂CH₂)₂N]—R²¹; especially those where R²¹ is        optionally substituted heteroaryl.    -   18. NR¹¹C(═O)OR²³; especially those where R²³ is optionally        substituted aryl.    -   19. NR¹¹C(═O)S—R¹⁸.    -   20. NR¹¹C(═O)NR¹¹R²³; especially those where R²³ is optionally        substituted aryl or optionally substituted heteroaryl.    -   21. NR¹¹C(═S)NR¹¹R²³; especially those where R²³ is optionally        substituted aryl.    -   22. NR¹¹S(═O)₂N(R¹⁵)₂.    -   23. NR¹¹C(═O)NR¹¹(alkylene)-R²⁴; especially those where R²⁴ is        optionally substituted heterocycloalkyl, or optionally        substituted heteroaryl.    -   24. NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B).    -   25. substituted alkyl, wherein one of the substituents is an        optionally substituted spirocycloalkyl group.    -   26. optionally substituted (alkylene)_(x)-cycloalkyl, especially        optionally substituted (C₁-alkylene)-cycloalkyl and optionally        substituted cycloalkyl.    -   27. optionally substituted -(alkylene)_(x)-heterocycloalkyl,        wherein the heterocycloalkyl does not include unsubstituted        N-morpholinyl, N-piperidyl, or N-thiomorpholinyl; especially        optionally substituted (C₁-alkylene)-heterocycloalkyl,        optionally substituted heterocycloalkyl, and more especially        optionally substituted heterocycloalkyl groups with two        heteroatoms, optionally substituted tetrahydrofuranyl and        optionally substituted tetrahydropyranyl.    -   28. NR¹¹R³², especially those where R³² is a phenyl group and        wherein the phenyl group is optionally substituted with one or        more alkoxy groups, and in particular, with one or more methoxy        groups.

The preceding paragraphs may be combined to further define additionalprefered embodiments of compounds of Formulas I-VI. For example, onesuch combination for R³, R⁴, R⁵, or R⁶ can include OR¹³, C(═O)R¹³,(CH₂)_(p)OR²², (CH₂)_(p)OR²², O-(alkylene)-R²⁷, OCH(CO₂R¹⁸)₂,OCH[(CH₂)_(p)OR²⁰]₂, and C(═O)-(alkylene)-R²⁵.

Another such combination includes NR¹¹R³², NR¹¹R³³, (alkylene)-NR¹⁸R¹⁹,C(R¹²)═N—R¹⁸, CH═N—OR¹³, C(R¹²)═N—OR²⁰,C(R¹¹)═N—NR¹¹C(═O)NR^(14A)R^(14B), C(R¹¹)═N—NR¹¹SO₂R¹⁸,OC(═O)NR¹¹(alkylene)-R²⁶, OC(═O)[N(CH₂CH₂)₂N]—R²¹, NR¹¹C(═O)OR²³,NR¹¹C(═O)S—R¹⁸, NR¹¹C(═O)NR¹¹R²³, NR¹¹C(═S)NR¹¹R²³, NR¹¹S(═O)₂N(R¹⁵)₂,NR¹¹C(═O)NR¹¹(alkylene)-R²⁴, and NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B).

A third such combination includes OR¹³, NR¹¹R³², NR¹¹R³³,(alkylene)-NR¹⁸R¹⁹, C(R¹²)═N—R¹⁸, CH═N—OR¹³, C(R¹²)═N—OR²⁰,OC(═O)NR¹¹(alkylene)-R²⁶, NR¹¹C(═O)NR¹¹R²³, NR¹¹C(═S)NR¹¹R²³,NR¹¹C(═O)NR¹¹(alkylene)-R²⁴, NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B),C(═O)-cycloalkyl, and optionally substituted-(alkylene)_(x)-heterocycloalkyl.

A fourth such combination includes OR¹³, C(═O)R¹³, (CH₂)_(p)OR²²,OCH(CO₂R¹⁸)₂, OCH[(CH₂)_(p)OR²⁰]₂, NR¹¹R³², NR¹¹R³³, (alkylene)-NR¹⁸R¹⁹,CH═N—OR¹³, C(R¹²)═N—OR²⁰, OC(═O)NR¹¹(alkylene)-R²⁶, NR¹¹C(═O)NR¹¹R²³,NR¹¹C(═O)NR¹¹(alkylene)-R²⁴, substituted alkyl, wherein the alkyl issubstituted with at least a spiroalkyl group, optionally substituted-(alkylene)_(x)-cycloalkyl, and optionally substituted-(alkylene)_(x)-heterocycloalkyl.

A fifth such combination includes NR¹¹R³², NR¹¹R³³, (alkylene)-NR¹⁸R¹⁹,C(R¹²)═N—R¹⁸, CH═N—OR¹³, C(R¹²)═N—OR²⁰,C(R¹¹)═N—NR¹¹C(═O)NR^(14A)R^(14B), C(R¹¹)═N—NR¹¹SO₂R¹⁸,OC(═O)NR¹¹(alkylene)-R²⁶, OC(═O)[N(CH₂CH₂)₂N]—R²¹, NR¹¹C(═O)OR²³,NR¹¹C(═O)S—R¹⁸, NR¹¹C(═O)NR¹¹R²³, NR¹¹C(═S)NR¹¹R²³, NR¹¹S(═O)₂N(R¹⁵)₂,NR¹¹C(═O)NR¹¹(alkylene)-R²⁴, NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B), substitutedalkyl, wherein the alkyl is substituted with at least a spiroalkylgroup, optionally substituted -(alkylene)_(x)-cycloalkyl, and optionallysubstituted -(alkylene)_(x)-heterocycloalkyl.

A sixth such combination includes NR¹¹R³³, and C(R¹²)═N—OR²⁰.

A seventh such combination includes NR¹¹R³², optionally substituted-(alkylene)_(x)-cycloalkyl, and optionally substituted-(alkylene)_(x)-heterocycloalkyl.

Other embodiments of the present invention include compounds of formulasI–VI wherein at least one of R³, R⁴, R⁵, or R⁶ is NR¹¹R³² wherein R³² isphenyl optionally substituted with one to three OR³⁰ groups,particularly those wherein R³⁰ is C₁–C₈ alkyl. Further embodimentsinclude those wherein R³² is phenyl substituted with one to threemethoxy groups, or those wherein R³² is phenyl substituted with twomethoxy groups.

In other aspects of the present invention, there are included compoundsof Formulas I–VI wherein at least one R³, R⁴, R⁵, and R⁶ is NR¹¹R³³,wherein R³³ is optionally substituted heteroaryl, or those wherein R³³is optionally substituted cycloalkyl, or those wherein R³³ is optionallysubstituted heterocycloalkyl. Other embodiments include those whereinR³³ is 5–6 membered heteroaryl ring with one to three nitrogen atoms inthe ring. Further embodiments include compounds wherein R³³ is a 6membered heteroaryl ring with two nitrogen atoms in the ring. Additionalembodiments include those wherein R³³ is pyrimidinyl, or those whereinR³³ is pyridazinyl, or those wherein R³³ is pyridyl.

The following terms and expressions used herein have the indicatedmeanings.

In the formulas described and claimed herein, it is intended that whenany symbol appears more than once in a particular formula orsubstituent, its meaning in each instance is independent of the other.

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50 mg” includes±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x–y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1–6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1–6” can include 1, 2, 3,4, 5, 6, 1–2, 1–3, 1–4, 1–5, 2–3, 2–4, 2–5, 2–6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, or branchedalkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups, such as alkoxy, alkoxycarbonyl, andalkylaminocarbonyl groups, has the same meaning as alkyl defined above.Lower alkyl groups, which are preferred, are alkyl groups as definedabove which contain 1 to 4 carbons. A designation such as “C₁–C₄ alkyl”refers to an alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon—carbon double bond. A designation “C₂–C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon—carbon triple bond. A designation “C₂–C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, the term “alkylene” refers to a branched or straightchained hydrocarbon of 1 to 8 carbon atoms, which is formed by theremoval of two hydrogen atoms. A designation such as “C₁–C₄ alkylene”refers to an alkylene radical containing from 1 to 4 carbon atoms.Examples include methylene (—CH₂—), propylidene (CH₃CH₂CH═),1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “phenylene” refers to a phenyl group with anadditional hydrogen atom removed, ie. a moiety with the structure of:

As used herein, the terms “carbocycle”, “carbocyclic” or “carbocyclyl”refer to a stable, saturated or partially saturated, monocyclic orbicyclic hydrocarbon ring system which is saturated, partially saturatedor unsaturated, and contains from 3 to 10 ring carbon atoms. Accordinglythe carbocyclic group may be aromatic or non-aromatic, and includes thecycloalkyl and aryl groups defined herein. The bonds connecting theendocyclic carbon atoms of a carbocyclic group may be single, double,triple, or part of a fused aromatic moiety.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. A designation such as “C₅–C₇ cycloalkyl” refers to a cycloalkylradical containing from 5 to 7 ring carbon atoms. Preferred cycloalkylgroups include those containing 5 or 6 ring carbon atoms. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

As used herein, the term “spirocycloalkyl” refers to a cycloalkyl groupbonded to a carbon chain or carbon ring moiety by a carbon atom commonto the cycloalkyl group and the carbon chain or carbon ring moiety. Forexample, a C₃ alkyl group substituted with an R group wherein the Rgroup is spirocycloalkyl containing 5 carbon atoms refers to:

As used herein, the term “aryl” refers to a mono- or bicyclichydrocarbon aromatic ring system having 6 to 12 ring carbon atoms.Examples include phenyl and naphthyl. Preferred aryl groups includephenyl or naphthyl groups. Included within the definition of “aryl” arefused ring systems, including, for example, ring systems in which anaromatic ring is fused to a cycloalkyl ring. Examples of such fused ringsystems include, for example, indane and indene.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a mono- di-, tri- or other multicyclic aliphaticring system that includes at least one heteroatom such as O, N, or S.The nitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups.

Some heterocyclic groups containing one or more nitrogen atoms includepyrrolidine, pyrroline, pyrazoline, piperidine, morpholine,thiomorpholine, N-methylpiperazine, indole, isoindole, imidazole,imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole,isothiazole, thiadiazole, triazine, isoxazole, oxindole, pyrazole,pyrazolone, pyrimidine, pyrazine, quinoline, iosquinoline, and tetrazolegroups. Some heterocyclic groups formed containing one or more oxygenatoms include furan, tetrahydrofuran, pyran, benzofurans,isobenzofurans, and tetrahydropyran groups. Some heterocyclic groupscontaining one or more sulfur atoms include thiophene, thianaphthene,tetrahydrothiophene, tetrahydrothiapyran, and benzothiophenes.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—, and includes ring systems whichcontain a saturated ring group bridged or fused to one or more aromaticgroups. Some heterocycloalkyl groups containing both saturated andaromatic rings include phthalamide, phthalic anhydride, indoline,isoindoline, tetrahydroisoquinoline, chroman, isochroman, and chromene.

As used herein, the term “heteroaryl” refers to an aryl group containing5 to 10 ring carbon atoms in which one or more ring carbon atoms arereplaced by at least one hetero atom such as —O—, —N—, or —S—. Someheteroaryl groups of the present invention include pyridyl, pyrimidyl,pyrrolyl, furanyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl,isoquinolyl, benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiazolylgroups.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, phenethyl, benzhydryl, diphenylmethyl,triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term “heteroarylalkyl” refers to an alkyl group thatis substituted with a heteroaryl group.

As used herein, the term “alkoxy” refers to an oxygen radicalsubstituted with an alkyl group. Examples include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc.

As used herein, the term “arylalkoxy” refers to an aryl-substitutedalkoxy group, such as benzyloxy, diphenylmethoxy, triphenylmethoxy,phenylethoxy, diphenylethoxy, etc.

As used herein, the term “alkylcarbonyloxy” refers to an RC(═O)O— group,wherein R is an alkyl group.

As used herein, the term “monosaccharide” refers to a simple sugar ofthe formula (CH₂O)_(n). The monosaccharides can be straight-chain orring systems, and can include a saccharose unit of the formula—CH(OH)-C(═O)—. Examples of monosaccharides include erythrose, threose,ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose,gulose, idose, galactose, talose, erythulose, ribulose, xyulose,psicose, fructose, sorbose, tagatose, erythropentulose, threopentulose,glycerotetrulose, glucopyranose, fructofuranose, etc.

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)-NH₂. The amino acids can be in their D, L orracemic configurations. Amino acids include naturally-occurring andnon-naturally occurring moieties. The naturally-occurring amino acidsinclude the standard 20 α-amino acids found in proteins, such asglycine, serine, tyrosine, proline, histidine, glutamine, etc.Naturally-occurring amino acids can also include non-α-amino acids (suchas β-alanine, γ-aminobutyric acid, homocysteine, etc.), rare amino acids(such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc.) andnon-protein amino acids (such as citrulline, ornithine, canavanine,etc.). Non-naturally occurring amino acids are well-known in the art,and include analogs of natural amino acids. See Lehninger, A. L.Biochemistry, 2^(nd) ed.; Worth Publishers: New York, 1975; 71–77, thedisclosure of which is incorporated herein by reference. Non-naturallyoccurring amino acids also include α-amino acids wherein the side chainsare replaced with synthetic derivatives. In certain embodiments,substituent groups for the compounds of the present invention includethe residue of an amino acid after removal of the hydroxyl moiety of thecarboxyl group thereof; i.e., groups of formula —C(═O)CH(sidechain)-NH₂. Representative side chains of naturally occurring andnon-naturally occurring α-amino acids include are shown below in TableA.

TABLE A H CH₃— HO—CH₂— C₆H₅—CH₂— HO—C₆H₄—CH₂—

HS—CH₂— HO₂C—CH(NH₂)—CH₂—S—S—CH₂— CH₃—CH₂— CH₃—S—CH₂—CH₂—CH₃—CH₂—S—CH₂—CH₂— HO—CH₂—CH₂— C₅H₉— C₆H₁₁— C₆H₁₁—CH₂— CH₃—CH(OH)—HO₂C—CH₂—NHC(═O)—CH₂— HO₂C—CH₂— HO₂C—CH₂—CH₂— NH₂C(═O)—CH₂—NH₂C(═O)—CH₂—CH₂— (CH₃)₂—CH— (CH₃)₂—CH—CH₂— CH₃—CH₂—CH₂—H₂N—CH₂—CH₂—CH₂— H₂N—C(═NH)—NH—CH₂—CH₂—CH₂— H₂N—C(═O)—NH—CH₂—CH₂—CH₂—CH₃—CH₂—CH(CH₃)— CH₃—CH₂—CH₂—CH₂— H₂N—CH₂—CH₂—CH₂—CH₂—

As used herein, the term “trk” refers to the family of high affinityneurotrophin receptors presently comprising trk A, trk B, and trk C, andother membrane associated proteins to which a neurotrophin can bind.

As used herein, the term “VEGFR” refers to the family of high affinityvascular endothelial growth factor receptors presently comprisingVEGFR1, VEGFR2, VEGFR3, and other membrane associated proteins to whicha VEGF can bind.

As used herein, the term “MLK” refers to the family of high affinitymixed lineage kinases presently comprising MLK1, MLK2, MLK3, MLK4α & β,DLK, LZK, ZAK α & β, and other serine/threonine kinases classifiedwithin this family.

As used herein, the terms “enhance” or “enhancing” when used to modifythe terms “function” or “survival” means that the presence of a compoundof the present invention has a positive effect on the function and/orsurvival of a trophic factor responsive cell compared with a cell in theabsence of the compound. For example, and not by way of limitation, withrespect to the survival of, e.g., a cholinergic neuron, a compound ofthe present invention would evidence enhancement of survival of acholinergic neuronal population at risk of dying (due to, e.g., injury,a disease condition, a degenerative condition or natural progression)when compared to a cholinergic neuronal population not presented withsuch a compound, if the treated population has a comparatively greaterperiod of functionality than the non-treated population. As a furtherexample, and again not by way of limitation, with respect to thefunction of, e.g., a sensory neuron, a compound of the present inventionwould evidence enhancement of the function (e.g. neurite extension) of asensory neuronal population when compared to a sensory neuronalpopulation not presented with such a compound, if the neurite extensionof the treated population is comparatively greater than the neuriteextension of the non-treated population.

As used herein, the terms “inhibit” or “inhibition” refer to a specifiedresponse of a designated material (e.g., enzymatic activity) iscomparatively decreased in the presence of a compound of the presentinvention.

As used herein, the terms “cancer” or “cancerous” refer to any malignantproliferation of cells in a mammal. Examples include prostate, benignprostate hyperplasia, ovarian, breast, brain, lung, pancreatic,colorectal, gastric, stomach, solid tumors, head and neck,neuroblastoma, renal cell carcinoma, lymphoma, leukemia, otherrecognized malignancies of the hematopoietic systems, and otherrecognized cancers.

As used herein the terms “neuron”, “cell of neuronal lineage” and“neuronal cell” refer to a heterogeneous population of neuronal typeshaving singular or multiple transmitters and/or singular or multiplefunctions; preferably, these are cholinergic and sensory neurons. Asused herein, the phrase “cholinergic neuron” means neurons of theCentral Nervous System (CNS) and Peripheral Nervous System (PNS) whoseneurotransmitter is acetylcholine; exemplary are basal forebrain andspinal cord neurons. As used herein, the phrase “sensory neuron”includes neurons responsive to environmental cues (e.g., temperature,movement) from, e.g., skin, muscle and joints; exemplary is a neuronfrom the DRG.

As used herein the term “trophic factor” refers to a molecule thatdirectly or indirectly affects the survival or function of a trophicfactor responsive cell. Exemplary trophic factors include CiliaryNeurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF),insulin and insulin-like growth factors (e.g., IGF-I, IGF-II, IGF-III),interferons, interleukins, cytokines, and the neurotrophins, includingNerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5(NT-4/5) and Brain Derived Neurotrophic Factor (BDNF).

As used herein the term “trophic factor-responsive cell” refers to acell which includes a receptor to which a trophic factor canspecifically bind; examples include neurons (e.g., cholinergic andsensory neurons) and non-neuronal cells (e.g., monocytes and neoplasticcells).

As used herein the terms “trophic factor activity” and “trophicfactor-induced activity”, refer to both endogenous and exogenous trophicfactors, where “endogenous” refers to a trophic factor normally presentand “exogenous” refers to a trophic factor added to a system. Asdefined, “trophic factor induced activity” includes activity induced by(1) endogenous trophic factors; (2) exogenous trophic factors; and (3) acombination of endogenous and exogenous trophic factors.

As used herein, the term “at risk of dying” in conjunction with abiological material, e.g., a cell such as a neuron, refers to a state orcondition which negatively impacts the biological material such that thematerial has an increased likelihood of dying due to such state orcondition. For example, compounds disclosed herein can “rescue” orenhance the survival of motoneurons which are naturally at risk of dyingin an in ovo model of programmed cell death. Similarly, for example, aneuron may be at risk of dying due to the natural aging process whichoccasions the death of a neuron, or due to an injury, such as a traumato the head, which may be such that neurons and/or glia, for example,impacted by such trauma may be at risk of dying. Further, for example, aneuron may be at risk of dying due to a disease state or condition, asin the case of neurons at risk of dying as occasioned by the diseaseALS. Thus, by enhancing the survival of a cell at risk of dying by useof a compound of the claimed invention is meant that such compounddecreases or prevents the risk of the death of the cell.

As used herein the term “contacting” refers to directly or indirectlycausing placement together of moieties, such that the moieties directlyor indirectly come into physical association with each other, whereby adesired outcome is achieved. Thus, as used herein, one can “contact” atarget cell with a compound as disclosed herein even though the compoundand cell do not necessarily physically join together (as, for example,is the case where a ligand and a receptor physically join together), aslong as the desired outcome is achieved (e.g., enhancement of thesurvival of the cell). Contacting thus includes acts such as placingmoieties together in a container (e.g., adding a compound as disclosedherein to a container comprising cells for in vitro studies) as well asadministration of the compound to a target entity (e.g., injecting acompound as disclosed herein into a laboratory animal for in vivotesting, or into a human for therapy or treatment purposes).

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of a particular disorder.

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can beprepared from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

As used herein, “prodrug” is intended to include any covalently bondedcarriers which release the active parent compound as defined in thepresent invention in vivo when such prodrug is administered to amammalian subject. Since prodrugs are known to enhance numerousdesirable qualities of pharmaceuticals (e.g., solubility,bioavailability, manufacturing, etc.) the compounds of the presentinvention may be delivered in prodrug form. Thus, the present inventioncontemplates prodrugs of the claimed compounds, compositions containingthe same, and methods of delivering the same. Prodrugs of a compound ofthe present invention may be prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Accordingly, prodrugs include, for example, compounds of thepresent invention wherein a hydroxy, amino, or carboxy group is bondedto any group that, when the prodrug is administered to a mammaliansubject, cleaves to form a free hydroxyl, free amino, or carboxylicacid, respectively. Examples include, but are not limited to, acetate,formate and benzoate derivatives of alcohol and amine functional groups;and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include their respective diastereomers or enantiomers. Thecompounds are normally prepared as racemates and can conveniently beused as such, but individual diastereomers or enantiomers can beisolated or synthesized by conventional techniques if so desired. Suchracemates and individual diastereomers or enantiomers and mixturesthereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof the present invention may contain protecting groups. For example, theamino acid side chain substituents of the compounds of the presentinvention can be substituted with protecting groups such asbenzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred groups for protectinglactams include silyl groups such as t-butyldimethylsilyl (“TBDMS”),dimethoxybenzhydryl (“DMB”), acyl, benzyl (“Bn”), and methoxybenzylgroups. Preferred groups for protecting hydroxy groups include TBS,acyl, benzyl, benzyloxycarbonyl (“CBZ”), t-butyloxycarbonyl (“Boc”), andmethoxymethyl. Many other standard protecting groups employed by oneskilled in the art can be found in Greene, T. W. and Wuts, P. G. M.,“Protective Groups in Organic Synthesis” 2d. Ed., Wiley & Sons, 1991.

Synthesis

The general routes to prepare the examples shown in Tables 1–3 of thepresent invention are shown in the Schemes 1–18. The intermediates usedto prepare the examples and their mass spectral data are shown in theTable B. The reagents and starting materials are commercially available,or readily synthesized by well-known techniques by one of ordinary skillin the arts. All processes disclosed in association with the presentinvention are contemplated to be practiced on any scale, includingmilligram, gram, multigram, kilogram, multikilogram or commercialindustrial scale. All substituents in the synthetic schemes, unlessotherwise indicated, are as previously defined.

TABLE B I-1399(M + 1)

I-2485(M + 1)

I-3448(M + 1)

I-4355(M + 1)

I-5439(M + 1)

I-6427(M + 1)

I-7428(M + 1)

I-8568(M + 1)

I-9490(M + 1)

I-10461(M +)

I-11390(M + 1)

I-12580(M + 1)

I-13369(M + 1)

I-14399(M + 1)

I-15414(M + 1)

I-16504(M + 1)

I-17464(M + 1)

I-18383(M − 1)

I-19339(M − 1)

I-20329(M + 1)

I-21399(M + 1)

I-22504(M + 1)

I-24371(M + 1)

I-25399(M + 1)

I-26

427 R (M + 1) 26-1: i-butyl 413 26-1: i-propyl (M + 1) 26-3: propyl 41326-4: butyl (M + 1) 26-5: ethyl 427 26-6: methyl (M + 1) 26-7:CH₂CH₂NMe₂ 399 26-8: CH₂CH₂NC₄H₈ (M + 1) 26-9: (CH₂)₆NC₄H₈ 385 (M +) 442(M + 1) 468 (M + 1) 524 (M + 1) I-27411(M + 1)

I-28

R 28-1: i-propyl 28-2: propyl 28-3: cyclopentyl 28-4: i-butyl I-29

I-30370(M + 1)

R 386 29-1: i-propyl (M + 1) 29-2: propyl 386 29-3: i-butyl (M + 1)29-4: butyl 400 (M + 1) I-31464(M + 1)

I-32385(M + 1)

R 31-1: cyclopentyl 31-2: i-butyl I-33

I-34329(M + 1)

R 373 33-1: ethyl (M + 1) 33-2: i-butyl 401 33-3: i-propyl (M + 1) 33-4:propyl 387 (M + 1) 387 (M + 1) I-35492(M + 1)

I-38427(M + 1)

I-37400(M + 1)

I-40311(M + 1)

I-41399(M + 1)

I-42411(M + 1)

The general procedures to prepare the pyrrolocarbazoles of the presentinvention are described in U.S. Pat. Nos. 5,705,511 (“the '511 patent”)and 6,630,500, PCT Publ. No. WO 00/47583, J. Heterocyclic Chemistry,2001, 38, 591, and J. Heterocyclic Chemistry, 2003, 40, 135. In general,the lactam nitrogen or intermediate alcohol groups of the intermediatesoutlined in Table B may be protected with such groups as acetyl,substituted silyl, benzyl, Boc, or dimethoxybenzhydrol.

Intermediate I-20 containing a 2-methyl-pyrazole F-ring, used to prepareexamples in Table 2, was prepared from the β-ketone,2-methyl-1,4,6,7-tetrahydro-5H-indazol-5-one (Peet, N. P.; LeTourneau,M. E.; Heterocycles, 1991, 32, 41) using methods described in the '511patent and in J. Heterocyclic Chemistry, 2003, 40, 135.

As shown in Scheme 1, the N1-methyl pyrazole derivatives in Table 3 wereprepared from the 1-methyl α-ketone (J. Chem. Res., 1986, 1401). TheN2-methyl pyrazole intermediates were prepared according to proceduresin J. Heterocyclic Chem. 1992, 19, 1355.

As outlined in Scheme 2, Examples 1–6 may be prepared from intermediateI-1 by converting the hydroxymethyl group, using trifluoroaceticanhydride, to an activated per-trifluoroacetate intermediate. Thisintermediate may be further reacted in situ with an alcohol, amine oramide to produce the appropriate product. In certain cases the alcoholmay serve as the solvent, otherwise suitable solvents also includemethylene chloride, dichloroethane or toluene. The hydroxymethylintermediates may be readily prepared by reduction of the correspondingaldehyde or ester intermediate as described in U.S. Pat. No. 6,630,500and herein. Alternatively the derivatives may be prepared by treatingthe hydroxymethyl intermediate I-1 with an acid catalyst, such ascamphor sulfonic acid, trifluoroacetic acid or p-toluene sulfonic acid,in the presence of the appropriate alcohol in a suitable solvent such asmethylene chloride or dichloromethane.

As outlined in Scheme 3, the heterocycloalkyl derivatives may beprepared by reacting the ester intermediate I-2 with ethanolamine.Longer chain amino alcohols, such as 3-aminopropanol and 4-aminobutanol,produce the corresponding ring-expanded six or seven-memberedheterocycloalkyl groups. Ethylene diamine and longer alkyl chaindiamines may be used to produce the analogous imidazoline andring-expanded diamine heterocycloalkyl derivatives.

As outlined in Scheme 4, Examples 9–11 and 328–329 were prepared byreacting an appropriate keto-ester intermediate, prepared using standardFriedel-Crafts acylation reactions (described in U.S. Pat. No. 6,630,500and herein) with a hydrazine or an N-substituted hydrazine derivative.

As outlined in Scheme 5, Example 8 was prepared from the(α,β-unsaturated ester (prepared by a Heck reaction with ethyl acrylate,described in the '511 patent) with hydrazine. An N-substituted hydrazinederivative may be used to produce the N-substituted derivative.

As outlined in Scheme 6, the cyclic acetal and cyclic thioacetalExamples 12–28 and 232–235 were prepared by reacting an aldehyde oralkyl-ketone intermediate with a ω-diol, di-thiol or hydroxyl-thiolreagent and an acid catalyst such as CSA or p-toluene sulfonic acid in asuitable aprotic solvent such as toluene, benzene, or NMP. The diol ordithiol reagent may have substitutions on the alkyl chain such as inExamples 14, 15, 18–24, and 28. The thioether derivatives may beconverted to sulfoxides or sulfones using standard oxidizing reagentssuch as hydrogen peroxide or mCPBA.

As outlined in Scheme 7, cycloalkyl and heterocycloalkyl ketonederivatives and cycloalkyl alkyl and heterocycloalkyl alkyl derivatives,such as in examples 32–38 may be prepared by treating the appropriatepyrrolocarbazole with an appropriate acid chloride, carboxylic acid,mixed carboxylic sulfonic anhydride or mixed carboxylic acid anhydride,in the presence of a Lewis acid catalyst such as AlCl₃, or FeCl₃ in asolvent such as methylene chloride, dichloroethane, nitromethane,nitrobenzene or carbon disulfide. The resulting ketone can be reduced tothe alcohol using standard reducing agents such as sodium borohydride(as in Example 37) or LiAlH₄. The hydroxy group of the cycloalkyl orheterocycloalkyl alcohols may be replaced with hydrogen by treatmentwith trifluoroacetic acid and triethyl silane (as in Example 38 and 309)in methylene chloride.

Scheme 8 outlines a route to heterocycloalkenyl derivatives, such asExamples 39–42. The alkene may be further reduced by standards chemicalor catalytic hydrogenation methods to the corresponding heterocycloalkylderivative.

Scheme 9 outlines a route for the preparation of substituted orunsubstituted 2-, 3-, or 4-piperdinyl derivatives, such as Example 43.From intermediate I-12, the pyridyl ring may be catalytically reduced tothe saturated piperidyl using a Raney nickel catalyst. Alternatively,using methods described for Examples 44 and 45, the piperidinyl may beincorporated by Stille or Suzuki coupling reactions using theappropriate piperidinyl stannane or borate and followed by a reductionto the saturated piperidinyl. The piperidinyl nitrogen may be alkylatedby standard alkylation reactions as described for Examples 46–48.Standard aryl or heteroaryl Stille and Suzuki coupling techniques mayalso be used to prepare fused heterocycloalkyl-aryl derivatives.

Scheme 10 outlines routes for the preparation of Examples 49–51 usingstandard methodologies.

Scheme 11 outlines the route to prepare carbamate-type derivatives, suchas Examples 52–53, and 404–422. An alternate method to preparing N,N-di-substituted carbamates utilized a nitrophenyl carbonateintermediate which may be treated with various primary or secondaryamines. Similarly urea, O-carbamate, and N-carbamate derivatives may beprepared from reaction of the appropriate amine or phenol intermediatewith an isocyanate or chloroformate or from the appropriate nitrophenylcarbonate, nitrophenyl carbamate, or trichloromethylcarbonyl (see J.Org. Chem. 2003, 68, 3733–3735). Ether derivatives, such as Examples60–67, may be prepared from the phenol intermediates using standardalkylation techniques known to those skilled in the art of organicsynthesis.

Scheme 12 shows a process for preparation of heterocycloalkyl lactonederivatives, such as Examples 68, 70–74. The intermediate keto-ester wasreduced to a hydroxyl-ester intermediate, which cyclizes to the lactone.

Schemes 13–15 outline preparations for cyclic ether derivatives. Thecyclic ether group was installed by formation of a keto-esterintermediate prepared through a standard Friedel-Crafts type acylationreaction (described in U.S. Pat. No. 6,630,500 and herein). The alkylspacer between the chlorocarbonyl and ester may be substituted orunsubstituted. The keto-ester was then reduced to the diol intermediateusing LiBH₄ in THF or NaBH₄ in ethanol. The ring may be closed bytreatment with an acid such as trifluoroacetic acid in dichloromethaneor dichloroethane. As shown in Scheme 14, the R² group could beincorporated after installation of the cyclic ether using a base and anelectrophile, or as shown in Scheme 15, the R² group may be installedfirst, followed by formation of the cyclic ether ring.

Scheme 16 outlines preparation of oxime and hydrazone derivatives (suchas Examples 29, 169, 236–286, and 277–300) from the appropriate aldehydeor ketone using standard procedures known in the art.

Scheme 17 shows preparation of arylamine derivatives, such as Examples287–306. The aryl amine reagent is coupled with the bromo intermediatefollowed by lactam formation using RaNi and hydrogen in DMF/MeOH.

Scheme 18 shows a route for the preparation of heteroarylaminederivatives, such as Examples 309–318. Amino intermediates I-29 and I-37were prepared by alkylation of the appropriate cyano-esters with theappropriate alkyl iodide or bromide followed by nitration, andsubsequent RaNi reduction to provide the amino-lactam. Reaction of theamino lactam intermediate with an appropriate heteroaryl bromide orchloride produced the desired compounds.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments as shown in thefollowing Tables 1–3. The compounds of Tables 1–3 show activity in thetargets described herein at concentrations ranging from 0.1 nM to 10 μM.These examples are given for illustration of the invention and are notintended to be limiting thereof.

TABLE 1

*R¹ is H unless otherwise noted Ex. No. R³ R² Q R⁵ 1

CH₂CH₂CH₂OH CH₂ H 2

CH₂CH₂CH₂OH CH₂ H 3

CH₂CH₂CH₂OH CH₂ H 4

CH₂CH₂CH₂OH CH₂ H 5

CH₂CH₂CH₂OH CH₂ H 6

CH₂CH₂CH₂OH CH₂ H 7

H CH₂CH₂ OMe 8

CH₂CH₂CH₂OH CH₂ H 9

H CH₂CH₂ OCH₃ 10

H CH₂CH₂ OCH₃ 11

H CH₂CH₂ OCH₃ 12

CH₂CH₂CH₂OH CH₂ H 13

CH₂CH₂CH₂OH CH₂ H 14

CH₂CH₂CH₂OH CH₂ H 15

CH₂CH₂CH₂OH CH₂ H 16

CH₂CH₂CO₂Et CH₂ H 17

CH₂CH₂CH₂OH CH₂ H 18

CH₂CH₂CO₂Et CH₂ H 19

CH₂CH₂CH₂OH CH₂ H 20

CH₂CH₂CH₂OH CH₂ H 21

CH₂CH₂CO₂Et CH₂ H 22

CH₂CH₂CH₂OH CH₂ H 23

CH₂CH₂CO₂Et CH₂ H 24

CH₂CH₂CH₂OH CH₂ H 25

CH₂CH₂CO₂Et CH₂ H 26

CH₂CH₂CH₂OH CH₂ H 27

CH₂CH₂CH₂OH CH₂ H 28

H CH₂CH₂ O^(i)Pr 29

CH₂CH₂OH CH₂CH₂ OCH₃ 30 NEC≡N(H)CH₂— CH₂CH₂OH CH₂CH₂ OCH₃ 31

CH₂CH₂OBn CH₂CH₂ OCH₃ 32

H CH₂CH₂ OCH₃ 33

H CH₂ H 34

H CH₂ H 35

CH₂CH₂CO₂Et CH₂ H 36

CH₂CH₂CH₂OC(═O)-cyclopropyl CH₂ H 37

CH₂CH₂CH₂OH CH₂ H 38

CH₂CH₂CH₂OH CH₂ H 39

CH₂CH₂CH₂OC(═O)CH₃ CH₂ H 40

CH₂CH₂CH₂OH CH₂ H 41

H CH₂CH₂ OiPr 42

H CH₂ H 43

CH₂CH₂CH₂OH CH₂CH₂ OCH₃ 44

CH₂CH₂CH₂OH CH₂ H 45

CH₂CH₂CH₂OH CH₂ H 46

CH₂CH₂CH₂OH CH₂ H 47

CH₂CH₂CH₂OH CH₂ H 48

CH₂CH₂CH₂OH CH₂ H 49

CH₂CH₂CH₂OCO—CH₃ CH₂ H 50

CH₂CH₂CH₂OH CH₂ H 51

CH₂CH₂CH₂OH CH₂ H 52

H CH₂CH₂ OiPr 53

H CH₂CH₂ OiPr 54

CH₂CH₂OH CH₂CH₂ OCH₃ 55

CH₂CH₂OBn*R¹ = CH(p-methoxyphenyl)₂ CH₂CH₂ OCH₃ 56

CH₂CH₂OBn CH₂CH₂ OCH₃ 57

CH₂CH₂OBn*R¹ = CH(p-methoxyphenyl)₂ CH₂CH₂ OCH₃ 58

CH₂CH₂OH CH₂CH₂ OCH₃ 59 F H CH₂CH₂

60

H CH₂CH₂ OiPr 61 H CH₂CH₂OH CH₂CH₂

62 H CH₂CH₂OH CH₂CH₂

63 H CH₂CH₂OH CH₂CH₂

64 H CH₂CH₂OH CH₂CH₂ O—CH(CO₂Me)₂ 65 H CH₂CH₂OH CH₂CH₂ OCH[(CH₂)₃—OEt]₂66 H

CH₂CH₂

67 H H CH₂CH₂

68

(CH₂)₃O₂C(CH₂)₂CO₂CH₃ CH₂ H 69

H CH₂CH₂ OCH₃ 70

H CH₂CH₂ OCH₃ 71

H CH₂CH₂ OCH₃ 72

H CH₂CH₂ OCH₃ 73

Et CH₂CH₂ OCH₃ 74

CH₂CH₂CH₂OH CH₂ H 75

H CH₂CH₂ OCH₃ 76

CH₂CH₂CH₂OH CH₂ H 77

CH₂CH₂CH₂OH CH₂ H 78

H CH₂ H 79

H CH₂ H 80

H CH₂CH₂ OCH₃ 81

CH₂CH₂OH CH₂CH₂ OCH₃ 82

CH₂CH₂OH CH₂CH₂ OCH₃ 83

CH₂CH₃ CH₂CH₂ OCH₃ 84

CH₂CH₃ CH₂CH₂ OCH₃ single isomer (−) 85

CH₂CH₃ CH₂CH₂ OCH₃ single isomer (+) 86

H CH₂ H 87

CH₂CH₂CH₂OH CH₂ H 88

CH₂CH₂CH₂OH CH₂ H 89

CH₂CH₂CH₂OH CH₂ H 90

CH₂CH₂CH₂OH CH₂ H 91

H CH₂ H 92

CH₂CH₂ CH₂ H 93

CH₂CH₂CH₃ CH₂ H 94

CH₃ CH₂ H 95

CH₂CH₂CH₂CH₂CH₃ CH₂ H 96

CH₂CH═CH₂ CH₂ H 97

CH₂CH₂CH₂CH₂CH₃ CH₂ H 98

CH₂CH₂CH₂CH₃ CH₂ H 99

CH₂CH₂NEt₂ CH₂ H 100

H CH₂CH₂ OCH₃ 101

H CH₂CH₂ OCH₃ 102

H CH₂CH₂ OCH₃ 103

H CH₂CH₂ OCH₃ 104

CH₂CH₂ OCH₃ 105

CH₃ CH₂CH₂ OCH₃ 106

(CH₂)₄CH₃ CH₂CH₂ OCH₃ 107

(CH₂)₅CH₃ CH₂CH₂ OCH₃ 108

(CH₂)₃CH₃ CH₂CH₂ OCH₃ 109

(CH₂)₂CH(CH₃)₂ CH₂CH₂ OCH₃ 110

CH₂CH═CH₂ CH₂CH₂ OCH₃ 111

CH₂CH₂CH₂OTBS CH₂CH₂ OCH₃ 112

CH₂CH₂CH₂OTHP CH₂CH₂ OCH₃ 113

CH₂CH₂CH₂OH CH₂CH₂ OCH₃ 114

CH₂CH₂NEt₂ CH₂CH₂ OCH₃ 115

CH₂CH₂ OCH₃ 116

CH₂CH₂ OCH₃ * and R¹ is

117

CH₂CH═CHEt CH₂CH₂ OCH₃ 118

CH₂CH₂CH₂CN CH₂CH₂ OCH₃ 119

CH₂CH₂CH₂ CH₂CH₃ OCH₃ 120

CH₂CH(CH₃)₂ CH₂CH₂ OCH₃ 121

CH₂OCH₃ CH₂CH₂ OCH₃ 122

CH₂CH₂ OCH₃ 123

CH₂CH₂F CH₂CH₂ OCH₃ 124

(CH₂)₃OTBS CH₂CH₂ OCH₃ 125

(CH₂)₃OH CH₂CH₂ OCH₃ 126

CH₂CH₂CH₃ CH₂CH₂ OCH₃ 127

(CH₂)₂OTBS CH₂CH₂ OCH₃ 128

(CH₂)₂OH CH₂CH₂ OCH₃ 129

CH₂CH₃ CH₂CH₂ OCH₃ 130

CH₂CH₂CH₂CN CH₂CH₂ OCH₃ 131

CH₃ CH₂CH₂ OCH₃ 132

CH₂CH₂ OCH₃ 133

CH₂C═CH CH₂CH₂ OCH₃ 134

H CH₂CH₂ OH 135

CH₂CH₃ CH₂CH₂ OH 136

H CH₂CH₂ OiPr 137

CH₂CH₂CH₃ CH₂CH₂ O^(n)Pr 138

H CH₂CH₂ O^(n)Pr 139

CH(CH₃)₂ CH₂CH₂ O^(i)Pr 140

CH₂CH₃ CH₂CH₂ OEt 141

H CH₂CH₂

142

H CH₂CH₂

143

CH₂CH₂CH₂CN CH₂CH₂ O—CH₂CH₂CH₂—CN 144

H CH₂CH₂ O(CH₂)₃CN 145

CH₂CH═CH₂ CH₂CH₂ OCH₂—CH═CH₂ 146

H CH₂CH₂ OCH₂—CH═CH₂ 147

H CH₂CH₂ O(CH₂)₄CN 148

(CH₂)₄CN CH₂CH₂ O(CH₂)₄CN 149

CH₂CH₂CH₂CN CH₂CH₂ O^(i)Pr 150

CH₃*R¹ is Me CH₂CH₂ O^(i)Pr 151

CH₃ CH₂CH₂ O^(i)Pr 152

CH(CH₃)CH₂CH₃ CH₂CH₂ O^(i)Pr 153

CH₂CH₂ O^(i)Pr 154

CH₂CH₃ CH₂CH₂ O^(i)Pr 155

CH₂CH₂F CH₂CH₂ O^(i)Pr 156

CH₂CH₂CH₂F CH₂CH₂ O^(i)Pr 157

CH₂CH₂CH₂CH₃ CH₂CH₂ O^(i)Pr 158

CH₂CH₂ O^(i)Pr 159

H CH₂CH₂ OH 160

CH₃ CH₂CH₂ OMe 161

CH₂CH₃ CH₂CH₂ OEt 162

H CH₂CH₂ OEt 163

H CH₂CH₂ OiPr 164

CH(CH₃)₂ CH₂CH₂ O^(i)Pr 165

CH₂CH₃ CH₂CH₂ O^(i)Pr 166

H CH₂CH₂ OCH₃ 167

CH₂CH₂CH₂OH CH₂ H 168

H CH₂ H 169

CH₂CH₂CH₂OH CH₂ H 170

CH₂CH₃ CH₂CH₂ OCH₃ 171

CH₂CH₃ CH₂CH₂ OCH₃

TABLE 2

*R¹ is H unless otherwise noted Ex. No. R³ R² Q 172

H CH₂CH₂ 173

H CH₂CH₂ 174

H CH₂CH₂ 175

H CH₂CH₂ 176

H CH₂CH₂ 177

CH₂CH₃ CH₂CH₂ 178

(CH₂)₃CN CH₂CH₂ 179

CH₂CH₂CH₃ CH₂CH₂ 180

CH₂CH₃ CH₂CH₂ 181

CH₃ CH₂CH₂ 182

(CH₂)₃OH CH₂CH₂ 183

CH₂CH═CH₂ CH₂CH₂ 184

CH₂CH₂OEt CH₂CH₂ 185

CH₂CH₂CH₂CH₃ CH₂CH₂ 186

CH₂CH₂OH CH₂CH₂ 187

CH₂CH₂ 188

CH(CH₃)₂ CH₂CH₂ 189

CH₂CH(CH₃)2 CH₂CH₂ 190

CH₂C≡CH CH₂CH₂ 191

CH₂CH₂NEt2 CH₂CH₂ 192

CH₂CH₂ 193

CH₂CH₂CH(CH₃)₂ CH₂CH₂ 194

CH₂CH₂CH₂CH₂CH₃ CH₂CH₂ 195

CH₂CH₂CH₂N(CH₃)₂ CH₂CH₂ 196

CH₂CH₂ 197

CH₂CH₂CH₂CH(CH₃)₂ CH₂CH₂ 198

CH₂CH₂CH₂CH₃ CH₂CH₂ single isomer 199

CH₂CH₂CH₂CH₃ CH₂CH₂ single isomer 200

CH₂CH₂CH₂F CH₂CH₂ 201

CH₂CH₂CH₂CH₂F CH₂CH₂ 202

iPr CH₂CH₂ single isomer 203

iPr CH₂CH₂ single isomer 204

CH₂CH₂ single isomer 205

CH₂CH₂ single isomer 206

CH₂CH═CMe₂ CH₂CH₂ 207

CH₂CH₂ 208

CH₂CH₂SEt CH₂CH₂ 209

H*R¹ is C(═O)CH₃ CH₂CH₂ 210

CH₂CH₂ 211

CH₂CH₂ 212

CH₂CH₂ 213

CH₂CH₂ 214

CH₂CH₂ 215

CH₂CH₂ 216

CH₂CH₂ 217

CH₂CH(CH₃)₂ CH₂CH₂ single isomer 218

CH₂CH(CH₃)₂ CH₂CH₂ single isomer 219

CH₂CH₂CH₂CN CH₂CH₂ 220

CH₂CH₃ CH₂CH₂ 221

CH₂CH₂CH₂CH₃ CH₂CH₂ 222

CH₃ CH₂CH₂ 223

CH₂CH═CH₂ CH₂CH₂ 224

CH₂CH₂CH₃ CH₂CH₂ 225

CH₂CH₂ 226

CH₂CH₂CH₂F CH₂CH₂ 227

CH₂CH₂CH₂CH₂F CH₂CH₂ 228

CH₂CH₃ CH₂CH₂ 229

CH₂CH₂CH₃ CH₂CH₂ 230

CH₂CH₃ CH₂CH₂ 231

CH₂CH₂CH₃CN CH₂CH₂ 232

H*R¹ is C(═O)CH₃ CH₂CH₂ 233

H CH₂CH₂ 234

H*R¹ is C(═O)CH₃ CH₂CH₂ 235

H CH₂CH₂ 236

H CH₂CH₂ 237

H CH₂CH₂ 238

H CH₂CH₂ 239

H CH₂CH₂ 240

H CH₂CH₂ 241

H CH₂CH₂ 242

H CH₂CH₂ 243

H CH₂CH₂ 244

H CH₂CH₂ 245

H CH₂CH₂ 246

CH₂CH(CH₃)₂ CH₂CH₂ 247

CH₂CH(CH₃)₂ CH₂CH₂ 248

CH₂CH(CH₃)₂ CH₂CH₂ 249

CH₂CH(CH₃)₂ CH₂CH₂ 250

CH₂CH(CH₃)₂ CH₂CH₂ 251

H CH₂CH₂ 252

CH(CH₃)₂ CH₂CH₂ 253

CH(CH₃)₂ CH₂CH₂ 254

CH(CH₃)₂ CH₂CH₂ 255

CH(CH₃)₂ CH₂CH₂ 256

CH₂CH(CH₃)₂ CH₂CH₂ 257

CH₂CH₂CH₃ CH₂CH₂ 258

CH₂CH₂CH₃ CH₂CH₂ 259

CH₂CH₂CH₂CH₃ CH₂CH₂ 260

CH₂CH₂CH₂CH₃ CH₂CH₂ 261

CH₂CH₂CH₂CH₃ CH₂CH₂ 262

CH₂CH₂CH₂CH₃ CH₂CH₂ 263

CH₂CH₃ CH₂CH₂ 264

CH₂CH₃ CH₂CH₂ 265

CH₂CH₃ CH₂CH₂ 266

CH₂CH₃ CH₂CH₂ 267

CH₂CH₃ CH₂CH₂ 268

CH₂CH(CH₃)₂ CH₂CH₂ 269

CH₂CH₂CH₃ CH₂CH₂ 270

CH₂CH₂CH₃ CH₂CH₂ 271

CH₃ CH₂CH₂ 272

CH₃ CH₂CH₂ 273

CH₃ CH₂CH₂ 274

CH₂CH₂NMe₂ CH₂CH₂ 275

CH₂CH₂NMe₂ CH₂CH₂ 276

CH₂CH₂NMe₂ CH₂CH₂ 277

CH₂CH(CH₃)₂ CH₂CH₂ 278

CH₂CH(CH₃)₂ CH₂CH₂ 279

CH₂CH₂ 280

CH₂CH₂ 281

CH₂CH₂ 282

CH₂CH₂ 283

CH₂CH₂ 284

CH₂CH₂ 285

CH₂CH₂ 286

CH₂CH₂ 287

CH(CH₃)₂ CH₂CH₂ 288

CH(CH₃)₂ CH₂CH₂ 289

CH(CH₃)₂ CH₂CH₂ 290

CH(CH₃)₂ CH₂CH₂ 291

CH(CH₃)₂ CH₂CH₂ 292

CH(CH₃)₂ CH₂CH₂ 293

CH₂CH₂CH₃ CH₂CH₂ 294

CH₂CH₂CH₃ CH₂CH₂ 295

CH₂CH₂CH₃ CH₂CH₂ 296

CH(CH₃)₂ CH₂CH₂ 297

CH(CH₃)₂ CH₂CH₂ 298

CH₂CH₂CH₃ CH₂CH₂ 299

CH₂CH₂ 300

CH₂CH₂CH₃ CH₂CH₂ 301

CH₂CH₂CH₃ CH₂CH₂ 302

CH₂CH₂CH₃ CH₂CH₂ 303

CH(CH₃)₂ CH₂CH₂ 304

CH₂CH(CH₃)₂ CH₂CH₂ 305

CH₂CH(CH₃)₂ CH₂CH₂ 306

CH(CH₃)₂ CH₂CH₂ 307

CH₂CH₂CH₃ CH₂CH₂ 308

CH₂CH(CH₃)₂ CH₂CH₂ 309

CH(CH₃)₂ CH₂CH₂ 310

CH₂CH₂CH₃ CH₂CH₂ 311

CH₂CH(CH₃)₂ CH₂CH₂ 312

CH(CH₃)₂ CH₂CH₂ 313

CH₂CH(CH₃)₂ CH₂CH₂ 314

CH(CH₃)₂ CH₂CH₂ 315

CH₂CH(CH₃)₂ CH₂CH₂ 316

CH₂CH(CH₃)₂ CH₂CH₂ 317

CH₂CH(CH₃)₂ CH₂CH₂ 318

CH₂CH₂CH₃ CH₂CH₂ 319

CH₂CH₂ 320

CH₂CH₂ 321

H CH₂CH₂ 322

H CH₂CH₂ 323

H CH₂CH₂ 324

H CH₂CH₂ 325

H CH₂CH₂ 326

H CH₂CH₂ 327

CH(CH₃)₂ CH₂CH₂ 328

H CH₂CH₂ 329

CH₂CH(CH₃)₂ CH₂CH₂ 330

CH₂CH(CH₃)₂ CH₂CH₂ 331

CH₂CH₂CH₃ CH₂CH₂ 332

CH₂CH₂CH₃ CH₂CH₂ 333

CH₂CH₂CH₃ CH₂CH₂ 334

CH₂CH₂CH₂CH₃ CH₂CH₂ 335

CH₂CH₂CH₃ CH₂CH₂ 336

CH₂CH₂CH₃ CH₂CH₂ 337

CH₂CH₂CH₂CH₃ CH₂CH₂ 338

CH₂CH₂CH₂CH₃ CH₂CH₂ 339

CH₂CH(CH₃)₂ CH₂CH₂ 340

CH₂CH(CH₃)₂ CH₂CH₂ 341

CH₂CH(CH₃)₂ CH₂CH₂ 342

CH₂CH(CH₃)₂ CH₂CH₂ 343

CH₂CH(CH₃)₂ CH₂CH₂ 344

CH₂CH(CH₃)₂ CH₂CH₂ 345

CH₂CH₂CH₃ CH₂CH₂ 346

CH₂CH(CH₃)₂ CH₂CH₂ 347

CH₂CH₂CH₂CH₃ CH₂CH₂ 348

CH₂CH₂CH₃ CH₂CH₂ 349

CH₂CH₂CH₃ CH₂CH₂ 350

CH₂CH₂CH₃ CH₂CH₂ 351

CH₂CH₂CH₃ CH₂CH₂ 352

CH₂CH₂CH₃ CH₂CH₂ 353

CH₂CH₂CH₃ CH₂CH₂ 354

CH₂CH₂CH₃ CH₂CH₂ 355

CH₂CH₃ CH₂CH₂ 356

CH(CH₃)₂ CH₂CH₂ 357

CH(CH₃)₂ CH₂CH₂ 358

CH₂CH₂CH₃ CH₂CH₂ 359

CH(CH₃)₂ CH₂CH₂ 360

CH₂CH₂CH₃ CH₂CH₂ 361

CH₂CH₂CH₃ CH₂CH₂ 362

CH(CH₃)₂ CH₂CH₂ 363

CH₂CH₂CH₃ CH₂CH₂ 364

CH₂CH₂CH₃ CH₂CH₂ 365

CH(CH₃)₂ CH₂CH₂ 366

CH(CH₃)₂ CH₂CH₂ 367

CH(CH₃)₂ CH₂CH₂ 368

CH(CH₃)₂ CH₂CH₂ 369

CH₂CH₂CH₃ CH₂CH₂ 370

CH₂CH₂CH₃ CH₂CH₂ 371

CH₂CH₂CH₃ CH₂CH₂ 372

CH₂CH₂CH₃ CH₂CH₂ 373

CH₂CH₂CH₃ CH₂CH₂ 374

CH₂CH₂CH₃ CH₂CH₂ 375

CH₂CH₂CH₃ CH₂CH₂ 376

CH₂CH₂CH₃ CH₂CH₂ 377

CH₂CH₂CH₃ CH₂CH₂ 378

CH₂CH₂CH₃ CH₂CH₂ 379

CH₂CH₂CH₃ CH₂CH₂ 380

CH(CH₃)₂ CH₂CH₂ 381

CH(CH₃)₂ CH₂CH₂ 382

CH(CH₃)₂ CH₂CH₂ 383

CH(CH₃)₂ CH₂CH₂ 384

CH₂CH(CH₃)₂ CH₂CH₂ 385

CH₂CH(CH₃)₂ CH₂CH₂ 386

CH₂CH(CH₃)₂ CH₂CH₂ 387

CH(CH₃)₂ CH₂CH₂ 388

CH(CH₃)₂ CH₂CH₂ 389

CH(CH₃)₂ CH₂CH₂ 390

CH(CH₃)₂ CH₂CH₂ 391

CH(CH₃)₂ CH₂CH₂ 392

CH(CH₃)₂ CH₂CH₂ 393

CH(CH₃)₂ CH₂CH₂ 394

CH(CH₃)₂ CH₂CH₂ 395

CH(CH₃)₂ CH₂CH₂ 396

CH₂CH₂CH₂CH₃ CH₂CH₂ 397

CH₂CH₂CH₂CH₃ CH₂CH₂ 398

CH₂CH₂CH₂CH₃ CH₂CH₂ 399

CH₂CH₂CH₃ CH₂CH₂ 400

CH₂CH₂CH₃ CH₂CH₂ 401

CH₂CH₂CH₃ CH₂CH₂ 402

CH₂CH₂CH₃ CH₂CH₂ 403

CH(CH₃)₂ CH₂CH₂ 404

CH₂CH₃ CH₂CH₂ 405

CH₂CH₃ CH₂CH₂ 406

CH₂CH₃ CH₂CH₂ 407

CH₂CH(CH₃)₂ CH₂CH₂ 408

CH₂CH(CH₃)₂ CH₂CH₂ 409

CH₂CH(CH₃)₂ CH₂CH₂ 410

CH₂CH(CH₃)₂ CH₂CH₂ 411

CH₂CH(CH₃)₂ CH₂CH₂ 412

CH₂CH(CH₃)₂ CH₂CH₂ 413

CH₂CH(CH₃)₂ CH₂CH₂ 414

CH₂CH(CH₃)₂ CH₂CH₂ 415

CH₂CH(CH₃)₂ CH₂CH₂ 416

CH₂CH(CH₃)₂ CH₂CH₂ 417

CH₂CH(CH₃)₂ CH₂CH₂ 418

CH₂CH(CH₃)₂ CH₂CH₂ 419

CH₂CH(CH₃)₂ CH₂CH₂ 420

CH₂CH(CH₃)₂ CH₂CH₂ 421

CH₂CH(CH₃)₂ CH₂CH₂ 422

CH(CH₃)₂ CH₂CH₂ 423

CH₂CH(CH₃)₂ CH₂CH₂ 424

CH(CH₃)₂ CH₂CH₂ 425

CH(CH₃)₂ CH₂CH₂ 426

CH₂CH(CH₃)₂ CH₂CH₂ 427

CH(CH₃)₂ CH₂CH₂ 428

CH₂CH(CH₃)₂ CH₂CH₂ 429

CH₂CH(CH₃)₂ CH₂CH₂ 430

CH₂CH(CH₃)₂ CH₂CH₂

TABLE 3

Ex. No. R³ R² Q 431

H CH₂CH₂ 432

CH₂CH₂CH₂CH₃ CH₂CH₂ 433

CH₂CH(CH₃)₂ CH₂CH₂ 434

CH₂CH₂ 435

CH₂CH₃ CH₂CH₂ 436

CH(CH₃)₂ CH₂CH₂ 437

CH₂CH₂CH₃ CH₂CH₂ 438

CH₃ CH₂CH₂ 439

CH₂CH₂ 440

CH₂CH₂OCH₂CH₃ CH₂CH₂ 441

CH₂CH₂CH₂OH CH₂CH₂ 442

CH₂CH₂OH CH₂CH₂ 443

CH(CH₃)₂ CH₂CH₂ 444

CH₂CH(CH₃)₂ CH₂CH₂ 445

CH₂CH(CH₃)₂ CH₂CH₂ 446

CH₂CH(CH₃)₂ CH₂CH₂ 447

CH₂CH(CH₃)₂ CH₂CH₂ 448

CH₂CH₃ CH₂CH₂

TABLE 4 MS m/e Example No. Structure (M + 1) 449

578 450

508 451

552 452

480 453

524 454

538 455

566 456

568 457

582 458

610 459

596 460

568 461

554 462

596 463

582 464

540 465

554 466

568 467

582 468

582 469

610 470

540 471

554General Procedure for Examples 1–3.

To a suspension of the diol intermediate I-1 (1 equivalent) in eitherthe appropriate alcohol, or the appropriate alcohol with eithermethylene chloride or chloroform, at room temperature in a reaction tubewas slowly added trifluoroacetic anhydride (1–2 equiv). The tube wasflushed with nitrogen and sealed tightly. The mixture was stirred atroom temperature for 1–2 hours then heated to 80° C. for 2–60 h andmonitored for disappearance of starting material by HPLC. Uponcompletion the reaction was allowed to cool to room temperature,concentrated and worked up by either triturating the residue with etheror collecting the resulting precipitate by filtration or extraction ofthe product from the reaction mixture with a suitable organic solvent.The solid product was purified by triturating with ether or by flashchromatography on silica gel using ethyl acetate or a mixture of ethylacetate and hexane.

Example 1

white solid ¹H NMR (DMSO-d₆): δ 0.87 (t, 6H), 1.50 (m, 4H), 1.93 (m,2H), 3.46 (m, 2H), 4.52 (s, 2H), 4.62 (s, 2H), 4.73 (m, 3H), 4.89 (s,2H), 7.37 (m, 2H), 7.48 (m, 1H), 7.66 (m, 2H), 7.91 (s, 1H), 8.54 (s,1H), 9.47 (d, 1H); MS (m/e) 469 (M+1).

Example 2

¹H NMR (DMSO-d₆): δ 0.89 (d, 6H), 1.47 (m, 2H), 1.70 (m, 1H), 1.96 (m,2H), 3.52 (m, 4H), 4.56 (s, 2H), 4.64 (s, 2H), 4.77 (m, 2H), 4.93 (s,2H), 7.40 (m, 2H), 7.51 (d, 1H), 7.69 (m, 2H), 7.94 (s, 1H), 8.58 (s,1H), 9.48 (d, 1H); MS (m/e) 469 (M+Na).

Example 3

¹H NMR (DMSO-d₆): δ 1.51 (m, 2H), 1.98 (m, 4H), 3.52 (m, 2H), 3.67 (m,1H), 3.84 (m, 2H), 4.58 (s, 2H), 4.73 (s, 2H), 4.79 (m, 4H), 4.95 (s,2H), 7.28–7.48 (m, 2H), 7.54 (d, 1H), 7.67–7.80 (m, 2H), 7.96 (s, 1H),7.60 (s, 1H), 9.51 (d, 1H); MS (ESI): m/e 505 (M+Na)⁺.

General Method for Examples 4–6

To a well-stirred suspension of intermediate diol I-1 (0.150 g, 0.37mmol) in 7 mL of methylene chloride were added sequentiallytrifluoroacetic anhydride (0.395 g, 1.88 mmol) and N-methyl morpholine(0.152 g, 1.5 mmol) at 5° C. and under argon atmosphere. The resultedsuspension was further stirred at room temperature for 3 h and the lowboiling solvents were removed under vacuum. The solid was suspended in70 mL of acetonitrile and the excess amine or amide was added thenrefluxed for 18 h and acetonitrile was removed under vacuum. The crudematerial was dissolved in a mixture of THF and MeOH (1:1 ratio, 7 mL)and treated with 10 mL of 0.5 M solution of NaOMe in MeOH. The reactionmixture was stirred at room temperature for 1 h and the low boilingsolvents were removed under vacuum and the reaction mixture was quenchedwith water. The solid was filtered, washed with water and dried toprovide the crude solid. The crude material was purified by silica gelcolumn chromatography using 5% MeOH in methylene chloride to obtain pureproduct.

Example 4

¹H NMR (CD₃)₂SO δ: 1.86–1.99 (m, 2H), 2.0–2.46 (m,m, 4H), 3.15 (t, 2H),3.35–3.47 (m, 2H), 4.45–4.52 (m, 4H), 4.71–4.73 (m, 2H), 4.88 (s, 2H),7.30–7.41 (m, 3H), 7.62–7.69 (m, 2H), 7.82 (s, 1H), 8.55 (s, 1H), 9.46(d, 1H); MS: m/e 466 (M+1).

Example 5

¹H NMR (CD₃)₂SO δ: 1.68 (br s, 4H), 1.90–1.92 (m, 2H), 2.11–2.14 (m,2H), 3.09–3.22 (m, 2H), 3.40–3.47 (m, 2H), 4.50 (s, 1H), 4.65–4.74 (m,4H), 4.87 (s, 2H), 7.32–7.41 (m, 3H), 7.61–7.68 (m, 2H), 7.81 (s, 1H),8.53 (s, 1H), 9.46 (d, 1H); MS: m/e 480 (M+1).

Example 6

¹H NMR (CD₃)₂SO δ: 1.91–193 (m, 2H), 3.42–3.46 (m, 2H), 4.50 (s, 2H),4.69–4.74 (m, 2H), 4.88 (s, 2H), 5.70 (s, 2H), 7.32–7.41 (m, 2H),7.57–7.63 (m, 2H), 7.73 (d, 1H), 8.14 (s, 1H), 8.59 (s, 1H), 9.26 (s,1H), 9.46 (d, 1H), 10.76 (S, 1H).

Example 7

To a stirred solution of ethanolamine (43.9 uL, 0.729 mmol) in THF (4mL) was added sodium hydride (17.5 mg, 0.729 mmol) at room temperatureunder nitrogen. The reaction mixture stirred for 1 hour and a solutionof ester intermediate I-2 (166 mg, 0.243 mmol) in THF (4 mL) was added.The mixture was stirred at room temperature overnight. The mixture wasquenched with water, extracted with methylene chloride and washed withwater and brine. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo to give a yellow residue. Theresidue was dissolved in methylene chloride and cooled to 0° C. in anice bath. Thionyl chloride (70.9 uL, 0.972 mmol) was slowly addeddropwise. The mixture became red-orange in color and was warmed to roomtemperature for 1.5 hours. The mixture was diluted with ethyl acetate,poured over ice and neutralized with solid potassium carbonate to pH 9.The solid precipitate which formed and was collected by filtration andpurified by preparative TLC on silica gel using 10% methanol/chloroformto give a yellowish-tan solid (10.3 mg, 10% yield). ¹H NMR (DMSO-d₆): δ2.85 (m, 2H), 3.03 (t, 2H), 3.82 (s, 3H), 4.00 (t, 2H), 4.45 (t, 2H),4.84 (s, 2H), 6.83 (d, 1H), 8.00 (d, 1H), 8.19 (d, 1H), 8.39 (s, 1H),11.91 (s, 1H); MS (ESI): m/e 424 (M+1)⁺.

Example 8

3-bromo intermediate I-3 (0.224 g), ethyl acrylate (170 uL),Pd(II)acetate (3.5 mg), tri(O)tolylphosphine (18.6 mg), and TEA (0.3 mL)in dry DMF (3.2 mL) were heated to 90° C. for 21 h. The grey coloredpowder that formed was collected and diluted with methylene chloride (15mL), washed with 2% citric acid and NaCl solution and dried. Evaporationof the solvent gave a dark brown gum, triturating gave an orange solid.¹H NMR showed the product. The vinyl ester intermediate (120 mg) wasmixed with 60 uL of hydrazine, in 200 uL of ethanol and heated to 70° C.for 3 h. The brown gum obtained was diluted with ethyl acetate. A darkcolored gum that settled out was discarded. The ethyl acetate solutionwas evaporated and a foamy solid was obtained. The HPLC showed thepresence of 60% product; MS m/e 453 (M+1)⁺.

Example 9

Step A. To a stirred suspension of aluminum chloride (0.47 g, 0.00353mol) in 1,2-dichloroethane (5 mL) was added 3-carbomethoxypropionylchloride (0.43 mL, 0.00353 mol). The reaction gradually becamehomogeneous. A suspension of intermediate I-4 (0.5 g, 0.00141 mol) wasadded to the mixture. The orange reaction mixture was heated to refluxovernight. The mixture was cooled to room temperature and poured overice and concentrated HCl was added. The mixture stirred for 30 min. andthe solid was collected by filtration (0.52 g, 79% yield).

Step B. To a stirred solution of the product from step A (40 mg, 0.08mmol) in DMF (5 mL) under nitrogen was added hydrazine (11.7 mL, 0.242mmol). The mixture was heated to reflux overnight and monitored fordisappearance of starting material by HPLC. The reaction mixture wascooled to room temperature and concentrated in vacuo to an oil. Theproduct was purified by preparative HPLC to give the product as a tansolid (22% yield). ¹H NMR (DMSO-d₆): δ 2.86 (m,2H), 3.02 (m, 2H), 3.14(t, 2H), 3.41 (t, 2H), 3.82 (s, 3H), 4.85 (s, 2H), 6.85 (d, 1H), 6.91(s, 1H), 7.59 (d, 1H), 7.94 (d, 1H), 8.19 (d, 1H), 8.26 (s, 1H), 8.34(s, 1H), 10.86 (s, 1H), 11.78 (s, 1H); MS (ESI): m/e 451 (M+1)⁺.

Example 10

The ester intermediate produced in step A Example 9, (110 mg, 0.222mmol) dissolved in DMF (3 mL) was placed in a sealed glass reactiontube. Methyl hydrazine (35.4 uL, 0.666 mmol) was added to the reactionmixture and the tube was sealed and heated to 80° C. for 96 h. Themixture was cooled to room temperature and the solvent removed in vacuoleaving a yellow oil. Water was added to the oil and a precipitateformed that was collected by filtration. The solid was purified bypreparative TLC chromatography on silica gel using 5%methanol/chloroform to give a tan solid (12% yield). ¹H NMR (DMSO-d₆): δ2.50 (t, 2H), 2.86 (m, 2H), 3.03 (m, 2H), 3.17 (t, 2H), 3.37 (s, 3H),3.82 (s, 3H), 4.86 (s, 2H), 6.83 (d, 1H), 6.91 (s, 1H), 7.60 (d, 1H),7.98 (d, 1H), 8.19 (d, 1H), 8.27 (s, 1H), 8.41 (s, 1H), 11.8 (s, 1H); MS(ESI): m/e 465 (M+1)⁺.

Example 11

This compound was prepared by a similar method in Example 9 using theester from step A (110 mg, 0.259 mmol) and 2-hydroxyethylhydrazine (52.6uL, 0.777 mmol). The reaction mixture was heated to 100° C. for 48 h.The reaction solvent was removed in vacuo leaving an orange oil that waspurified by preparative TLC chromatography on silica gel using 10%methanol/chloroform to give a yellow solid (38 mg, 30% yield). ¹H NMR(DMSO-d₆): δ 2.56 (dd, 2H), 2.85 (dd, 2H), 3.02 (dd, 2H), 3.16 (dd, 2H),3.67 (dd, 2H), 3.85 (dd, 2H), 3.82 (s, 3H), 4.69 (t, 1H), 4.86 (s, 2H),6.83 (d, 1H), 6.91 (s, 1H), 7.61 (d, 1H), 7.99 (d, 1H), 8.20 (d, 1H),8.26 (s, 1H), 8.41 (s, 1H), 11.79 (s, 1H); MS (ESI): m/e 495 (M+1)⁺.

Synthesis of Aldehyde Intermediate I-5.

To a suspension of the indenocarbazole intermediate I-40 (8.0 g, 0.258mol) in acetonitrile (300 mL) at room temperature under nitrogen wasadded ethyl acrylate (4.19 mL, 0.387 mol) followed by1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.93 mL, 0.013 mol). Afteraddition of DBU, the reaction changed colors from orange to green. Thereaction mixture was heated to reflux overnight. The mixture remainedheterogeneous throughout the course of the reaction and became dark incolor. A small aliquot was removed after 18 h and the solid wascollected by filtration. ¹H NMR of the sample showed no startingmaterial remaining. The reaction mixture was cooled to room temperatureand the solid was collected by filtration. The solid was washed severaltimes with cold acetonitrile and dried in vacuo at 55° C. to yield alight orange solid (5.4 g, 78% yield). ¹H NMR (DMSO-d₆): δ 9.72 (t, 3H,J=6.8), 2.87 (m, 2H), 3.89 (q, 2H, J=6.8), 4.49 (s, 2H), 4.88 (s, 2H),4.92 (m, 2H), 7.29–7.48 (m, 3H), 7.50–7.73 (m, 3H), 7.96 (d, 1H,J=7.33), 8.56 (s, 1H), 9.47 (d, 1H, J=7.33). To a well stirredsuspension of the ester intermediate (10 g, 24.3 mmol) and1,1-dichloromethyl methylether (55.6 g, 488 mmol) in a mixture ofmethylene chloride (250 mL) and toluene (40 mL) was added tin(IV)chloride (95.1 g, 365 mmol) (1 M solution in methylene chloride). After4.5 h of reaction at room temperature, the reaction was quenched withaqueous 2N HCl (150 mL) and methylene chloride and toluene were removedunder vacuum. To the crude residue, an additional amount of 2N HCl (350mL) and t-butylmethyl methyl ether (200 mL) was added. The resultedsuspension was further stirred at room temperature for 14 h andfiltered, washed with t-butylmethyl methylether. The crude material wassuspended in a mixture of ethyl acetate (125 mL) and tetrahydrofuran(125 mL) and stirred for 14 h at room temperature then filtered andwashed with cold ethyl acetate to obtain 8.4 g of aldehyde. (79% yield).¹H NMR: (DMSO-d₆) δ: 0.98 (t, 3H), 2.92 (t, 2H), 3.88 (q, 2H), 4.65 (s,2H), 4.92–5.08 (m, 4H), 7.25–7.45 (m, 2H), 7.75 (d, 1H), 7.85 (d, 1H),8.05 (d, 1H), 8.52 (s, 1H), 8.69 (s, 1H), 8.95 (s, 1H), 10.18 (s, 1H);MS m/e 439 (M+1).

General Procedure for Cyclic Acetals and Thioacetal Examples 12–28.

A mixture of intermediate I-5 (0.2 g, 0.45 mmol), the diol or thiol(>4.5 mmol), p-toluenesulfonic acid (0.13 g, 0.68 mmol) and amberlyst (1g) in a mixture of 1-methyl-2-pyrrolidinone (3 mL) and toluene (25 mL)was refluxed using Dean-Stark apparatus for 2 days and under argonatmosphere. The reaction mixture was filtered, washed with1-methyl-2-pyrrolidinone and THF then concentrated. The oily liquid wasquenched with aq. saturated NaHCO₃ solution and the solid was filtered,washed with water to provide the crude material, which was purified bysilica gel column chromatography to furnish pure products. The product(1 mmol) was dissolved in THF (4 mL) and was added lithium borohydride(5 mmol) (1M solution in THF) at 0° C. then stirred at room temperaturefor 14 h. The reaction was quenched with aqueous NaHCO₃ solution andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried and concentrated to yield the crude product,which was purified by silica gel column chromatography to provide pureproduct.

Example 12

¹H NMR, (DMSO-d₆) δ: 1.82–2.00 (m, 2H), 3.42–3.55 (m, 2H), 3.95 (t, 2H),4.12 (t, 2H), 4.51 (s, 2H), 4.65–4.80 (m, 2H), 4.91 (s, 2H), 5.90 (s,2H), 7.32–7.45 (m, 2H), 7.55–7.70 (m, 2H), 7.80 (d, 1H), 7.98 (s, 1H),8.58 (s, 1H), 9.48 (d, 1H); MS m/e: 441 (M+1).

Example 13

¹H NMR, (DMSO-d₆) δ: 1.82–1.95 (m, 2H), 3.42–3.62 (m, 2H), 3.95 (t, 2H),4.25–4.39 (d,d, 2H), 4.65 (s, 2H), 4.63–4.72 (m, 2H), 4.89 (s, 2H), 5.72(s, 1H), 7.32–7.55, (s, 2H), 7.68 (d, 1H), 7.69–7.82 (m, 2H), 7.96 (s,1H), 8.55 (s, 1H), 9.48 (d, 1H); MS m/e 455 (M+1).

Example 14

¹H NMR, (DMSO-d₆) δ: 0.80 (s, 3H), 1.28 (s, 3H), 1.97–2.33 (m, 2H),3.40–3.52 (m, 2H), 3.69–3.76 (d,d 4H), 4.55 (s, 2H), 4.73–4.77 (m, 2H),4.93 (s, 2H), 5.62 (s, 1H), 7.35–7.45 (m, 2H), 7.62–7.68 (m, 2H), 7.74(d, 1H), 8.01 (s, 1H), 8.51 (s, 1H), 9.51 (d, 1H); MS m/e 483 (M+1).

Example 15

¹H NMR, (DMSO-d₆) δ: 1.19–1.38 (4xd, 6H), 1.96–1.99 (m, 2H), 3.41–3.53(m, 2H), 3.82–3.87 (m, 2H), 4.55 (s, 2H), 4.72–4.79 (m, 2H), 4.94 (s,2H), 6.10 (s, 1H), 7.35–7.44 (m, 2H), 7.61–7.68 (m, 2H), 7.75 (d, 1H),8.02 (s, 1H), 8.53 (s, 1H), 9.51 (d, 1H); MS m/e 469 (M+1).

Example 16

MS m/e 529 (M+1).

Example 17

MS m/e 487 (M+1).

Example 18

MS m/e 609 (M+1).

Example 19

MS m/e 567 (M+1).

Example 20

MS m/e 511 (M+1).

Example 21

MS m/e 557 (M+1).

Example 22

MS m/e 515 (M+1).

Example 23

MS m/e 539 (M+1).

Example 24

MS m/e 497 (M+1).

Example 25

MS m/e 515 (M+1).

Example 26

MS m/e 473 (M+1).

Example 27

MS m/e 471 (M+1).

Example 28

MS m/e 497 (M+1).

Example 29

To intermediate I-6 (30 mg, 0.07 mmol) in pyridine (0.5 mL) was addedO-(tetrahydro-2H-pyran-2yl)hydroxylamine (33 mg, 0.282 mmol, 4 eq) andthe reaction was heated to 100° C. overnight. The reaction wasconcentrated in vacuo, stirred with water, the product collected anddried at 80° C. ¹H NMR (400 MHz, DMSO) 8.52(1H, s), 8.42(1H, s),8.17(1H, s), 7.89(1H, d), 7.81(1H, d), 7.74(1H, d), 6.91(1H, s),6.82(1H, d), 5.35(1H, s), 5.01(1H, t), 4.81(2H, s), 4.68(2H, d),3.86(6H, m), 3.56(1H, m), 3.30(2H, m), 2.79(2H, m), 1.90(2H, m),1.68(4H, m) MS m/e 526 (M+1)⁺

Example 30

The amino methyl intermediate I-7 (50 mg, 0.11 mmol) was added to astirred solution of 10.65 μl cyanogen bromide (0.11 mmol) in dry ether(1 mL) at −20° C. containing anhydrous sodium carbonate (23 mg, 0.22mmol, 2 eq). The mixture is stirred for 2 hours then allowed to warm to0° C., and excess cyanogen bromide and sodium carbonate were then added.The reaction was allowed to warm to room temperature with stirringovernight and then concentrated. The residue was dissolved in ethylacetate, washed with water and brine, dried over magnesium sulfate,filtered and evaporated. The sample was dissolved in DMF, suspended onsilica gel, concentrated and then chromatographed on silica gel withmethanol/methylene (95/5 increasing to 9/1). The fractions containingproduct were concentrated and then the residue triturated with ether,collected and dried. ¹H NMR (DMSO-d₆) δ 8.40(1H, s), 7.95(1H, s),7.85(1H, d), 7.72(1H, d), 7.50(1H, d), 7.29(1H, m), 6.90(1H, s),6.75(1H, d), 4.98(1H, m), 4.78(2H, s), 4.65(3H, m), 4.25(2H, d),3.83(3H, m), 3.32(1H, m), 2.75(2H, m), 1.30(6H, d) MS m/e=481 (M+1)⁺

Example 31

To a stirred solution of intermediate I-8 (3.46 g, 7.1 mmol) in DMF (30mL) under nitrogen was added vinyl tributyltin (3.11 mL, 0.0113 mol) anddichlorobis(triphenylphosphine)-palladium (0.49 g, 0.00071 mol). Themixture was heated at reflux overnight then cooled to room temperature,filtered through celite and concentrated in vacuo to a dark oil. Thisoil was triturated with ether and the resulting precipitate wascollected and purified by flash chromatography on silica gel usinghexane/ethyl acetate (1:1) then ethyl acetate (100%) to give a yellowsolid (2.3 g, 63% yield). MS (ESI): m/e 515 (M+1)⁺. To a stirredsolution of this product (0.44 g, 0.855 mmol) in THF (10 mL) at roomtemperature under nitrogen was added osmium tetroxide 8.55 mL, 0.855mmol, 0.1 M solution) and pyridine (0.55 mL, 6.84 mmol). The reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with methylene chloride and washed with aqueous sodiumbicarbonate solution. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo to a yellow solid which waspurified by flash chromatography on silica gel to give a yellow solid(0.33 g, 72% yield). MS (ESI): m/e 549 (M+1)⁺. To a stirred suspensionof this diol (83 mg, 0.151 mmol) in benzene (8 mL) was added1,1′-carbonyldiimidazole (48.9 mg, 0.302 mmol). The reaction mixture washeated at reflux overnight then cooled to room temperature. The solventwas removed in vacuo to give a tan solid that was triturated with waterand collected by filtration. The solid was purified by preparative TLCchromatography on silica gel using 5% methanol/chloroform to give alight tan solid (25% yield). ¹H NMR (DMSO-d₆): δ 2.73 (m, 2H), 3.25 (m,4H), 3.82 (s, 3H), 3.85 (m, 2H), 4.35 (s, 2H), 4.64 (t, 1H), 4.75 (s,2H), 4.94 (t, 1H), 6.11 (t, 1H), 6.82 (d, 1H), 6.89 (s, 1H), 7.15 (d,3H), 7.63 (d, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 8.12 (s, 1H), 8.46 (s,1H), MS (ESI): m/e 575 (M+1)⁺, 597 (M+Na)⁺.

Example 32

To a stirred suspension of aluminum chloride (0.23 g, 1.76 mmol) in1,2-dichloroethane (5 mL) at room temperature under nitrogen was added3-oxabicyclo[3.1.0]hexane-2,4-dione (0.19 g, 1.76 mmol) in1,2-dichloroethane (3 mL). The mixture gradually became homogeneous anda suspension of I-4 (0.25 g, 0.705 mmol) in 1,2-dichloroethane (3 mL)was added. The reaction mixture was heated to 60° C. overnight.Additional acylating agent (2 equivalents) was prepared and added to thereaction mixture. The mixture continued to be heated at 60° C. for anadditional hour. The mixture was poured over ice and concentrated HClwas added. The resulting precipitate was collected by filtration andpurified by preparative TLC chromatography on silica gel using 10%methanol/chloroform to give a yellowish-tan solid (70% yield). ¹H NMR(DMSO-d₆): δ 1.24 (m, 1H), 1.58 (m, 1H), 2.31 (m, 1H), 2.41 (m, 1H),2.86 (m, 2H), 3.03 (m, 2H), 3.82 (s, 3H), 4.86 (q, 2H), 6.83 (d, 1H),6.92 (s, 1H), 7.62 (d, 1H), 8.13 (d, 1H), 8.20 (d, 1H), 8.45 (s, 1H),8.62 (s, 1H), 12.02 (s, 1H); MS (ESI): m/e 467 (M+1)⁺, 489 (M+Na)⁺.

Examples 33–36 were prepared using the general method of Example 32.

Example 33

MS (ESI): m/e 467 (M+1)⁺

Example 34

MS (ESI): m/e 407 (M+1)⁺

Example 35

MS (ESI): m/e 479 (M+1)⁺

Example 36

MS (ESI): m/e 505 (M+1)⁺

Example 37

This compound was prepared by sodium borohydride reduction of Example36. MS (ESI) m/e 439 (M+1)⁺.

Example 38

This compound was prepared by treating Example 37 with TFA andtriethylsilane in CH₂Cl₂. MS (ESI) m/e 423 (M+1)⁺.

Example 39

Bromo intermediate I-9 (68 mg, 0.139 mmol), tributylstannyl dioxene (104mg, 0.277 mmol), and bis(triphenylphosphine)palladium dichloride (5 mg)were combined in 2 mL anhydrous N,N-dimethylformamide and heated at 80°C. for 16 h. The mixture was concentrated onto 700 mg silica and appliedto a bed of silica. Medium pressure liquid chromatography employing agradient of 1–3% methanol:dichloromethane afforded 47 mg of a yellowsolid. NMR (DMSO-d₆) δ 9.55 (d, 1H), 8.6 (s, 1H), 7.95 (s, 1H), 7.6–7.75(m, 3H), 7.3–7.45 (m, 2H), 7.05 (s, 1H), 5.0 (s, 2H), 4.75 (t, 2H), 4.58(s, 2H), 4.3 (br s, 2H), 4,15 (m, 4H), 2.15 (m, 2H), 2.05 (s, 3H). MS(ES+): 495 (M+1).

Example 40

Approximately 40 mg of Example 39 was stirred for three hours and thenheated to reflux for two hours with 40 mg potassium carbonate in 50 mLmethanol:water (25:1). The solution was concentrated to approximately 5mL. 10 mL water was added and the solution was cooled to 0° C. and theproduct collected by filtration. The white-yellow solid was washed withwater and dried in vacuo to afford 28 mg of the product. NMR (DMSO-d₆) δ9.55 (d, 1H), 8.6 (s, 1H), 7.95 (s, 1H), 7.6–7.75 (m, 3H), 7.35–7.5 (m,2H), 7.05 (s, 1H), 5.0 (s, 2H), 4.8 (br s, 2H), 4.6 (s, 2H), 4.35 (br s,2H), 4.17 (br s, 2H), 3.53 (br s, 2H), 2.0 (m, 2H).

Example 41

In a sealed reaction tube, bromo intermediate I-10 (50 mg, 0.109 mmol)in DMF (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (4mg, 0.005 mmol, 5 mol %) and2-(tributylstannyl)-5,6-dihydro-[1,4]-dioxin (82 mg, 0.218 mmol) andheated to 90° C. overnight. The DMF was removed at reduced pressure andthe residue dissolved in ethyl acetate, washed with sodium bicarbonate,brine, and then dried over magnesium sulfate. The drying agent wasremoved by filtration and the solvent evaporated. The product waspurified by chromatography on silica gel using ethyl acetate/hexanes(70% increasing to 100% ethyl acetate). The fractions containing productwere concentrated and the solid obtained was dried at 80° C. for 12hours. MS m/e 467 (m+1)⁺.

Example 42

This compound was prepared in the same manner as Example 41 using bromointermediate I-11. ¹H NMR (DMSO-d₆) 11.90(1H, s), 9.22(1H, d), 8.41(1H,s), 7.92(1H, m), 7.53(2H, s), 7.28(1H, s), 6.98(2H, m), 4.92(2H, s),4.30(2H, m), 4.10(4H, m), 3.89(3H, s). MS m/e 425 (m+1)⁺.

Example 43

To intermediate I-12 (100 mg) in DMF (1 mL) was added palladiumhydroxide (5 mg) and one drop of concentrated HCl. The reaction mixturewas hydrogenated on a Parr apparatus at 50 psi for 5 hours. The catalystwas removed by filtration and the solvent concentrated in vacuo. Thesolid obtained was triturated with ether, collected and dried. MS m/e496 (M+1)⁺.

Example 44

This compound was prepared in a similar manner as Example 40 usingintermediate I-9 and 1,2,5,6-tetrahydropyridine-4-boronic acid. MS m/e450 (M+1)⁺.

Example 45

This compound was prepared from Example 44 by hydrogenation overpalladium on carbon. MS m/e 452 (M+1)⁺.

Example 46–48 were prepared from Example 45 by treatment with theappropriate electrophile.

Example 46

MS m/e 452 (M+1)⁺.

Example 47

MS m/e 530 (M+1)⁺.

Example 48

MS m/e 559 (M+1)⁺.

Example 49

Step A: To a well-stirred suspension of intermediate I-13 (4.4 g, 11.9mmol) in a mixture of 1-methyl-2-pyrrolidinone (51 mL) and methylenechloride (51 mL) were added sequentially triethylamine (2.99 g, 29.6mmol), a catalytic amount of 4-(dimethylamino)pyridine (0.2 g) andacetic anhydride (3.04 g, 29.8 mmol) at room temperature. After 16 hoursat room temperature, the reaction was quenched with water (150 mL) andthe methylene chloride was removed under vacuum. The solid was filtered,washed with water and dried to provide product (4.5 g, 90% yield). ¹HNMR, (DMSO-d₆) δ: 2.01 (s, 3H), 2.06–2.18 (m, 2H), 4.06–4.16 (m, 2H),4.51 (s, 2H), 4.75–4.87 (m, 2H), 4.92 (s, 2H), 7.27–7.78 (m, 6H), 8.00(d, 1H), 8.54 (s, 1H), 9.51 (d, 2H).

Step B: To a well stirred suspension of the product from step A (0.5 g,1.21 mmol) and 1,1-dichloromethyl methylether (1.39 g, 12.19 mmol) in amixture of methylene chloride (42 mL) and toluene (5 mL) was addedtin(IV) chloride (2.37 g, 9.11 mmol), (1 M solution in methylenechloride) at room temperature. The reaction was further stirred at roomtemperature for 4 h and at 50° C. for 45 min., then quenched thereaction at room temperature with aqueous 2N HCl (25 mL). Methylenechloride was removed under vacuum and the aqueous layer was trituratedwith t-butylmethyl methyl ether (30 mL) at room temperature for 14 h.The solid was filtered, washed with water and t-butylmethyl methyl etherthen dried to obtain the crude product, which was triturated witht-butylmethyl methyl ether (20 mL) to afford product, (0.43 g, 81%yield,). ¹H NMR, (DMSO-d₆) δ: 2.00 (s, 3H), 2.15–2.27 (m, 2H), 4.10–4.16(m, 2H), 4.48 (s, 2H), 4.76–4.90 (m, 2H), 4.95 (s, 2H), 7.33–7.45 (m,2H), 7.64 (d, 1H), 7.89 (d, 1H), 8.04 (d, 1H), 8.51 (s, 1H), 8.64 (s,1H), 9.51 (d, 1H), 10.11 (s, 1H); MS: m/e 439 (M+1).

Step C: A mixture of the product from step B (0.7 g, 1.6 mmol),N-methylhydroxylamine. HCl (1.06 g, 12.7 mmol), and sodium carbonate(1.18 g, 11.1 mmol) in 1-methyl-2-pyrrolidinone (13 mL) was heated to80° C. for 18 h. The reaction was quenched with water (80 mL) at roomtemperature and the solid was filtered, washed with water and dried toobtain product (0.68 g, 91% yield). ¹H NMR, (DMSO-d₆) δ: 2.01 (s, 3H),2.18–2.50 (m, 2H), 3.82 (s, 3H), 4.10–4.13 (m, 2H), 4.53 (s, 2H)4.78–4.79 (m, 2H), 4.91 (s, 2H), 7.39–7.44 (m, 2H), 7.66–7.68 (d, 1H),7.79 (d, 1H), 8.00 (s, 1H), 8.31 (d, 1H), 8.59 (s, 1H), 9.16 (s, 1H),9.50–9.52 (d, 1H); MS m/e 468 (M+1).

Step D: A mixture of the product from step C (0.1 g, 0.21 mmol) andallyl acetate (4 mL) in 1-methyl-2-pyrrolidinone (1.5 mL) was heated to100° C. for 20 h and the allyl acetate was removed under vacuum. Thereaction was quenched with water (74 mL) and the solid was filtered,washed with water, then dried to provide the crude product, which wastriturated with a mixture of tetrahydrofuran (1 mL) and diethyl ether(20 mL) to furnish Example 49 (0.08 g, 66% yield); MS m/e 568 (M+1).

Example 50

To a well stirred solution of Example 49 (0.195 g, 0.34 mmol) intetrahydrofuran (1 mL) was added methanolic ammonia (25 mL) then heatedto 80° C. for 14 h. The reaction was concentrated to ˜2 mL and ethylether was added slowly. The solid was filtered, washed with diethylether and dried to provide Example 50 (89 mg, 53% yield); MS m/e 484(M+1).

Example 51

A mixture of the product from step C, Example 49 (0.171 g, 0.364 mmol)and acrylonitrile (5 mL) in 1-methyl-2-pyrrolidinone (1 mL) was heatedto 100° C. for 14 h. Acrylonitrile was removed under vacuum and thecrude product was purified by silica gel column chromatography to obtainthe required product (0.150 g, 79% yield). The product was suspended intetrahydrofuran (2 mL) and treated with methanolic ammonia (15 mL) thenheated to 70° C. for 24 hour. Methanol was removed under vacuum and thecrude material was purified by silica gel column chromatography toobtain product (25 mg, 18% yield). MS: m/e 479 (M+1).

General Procedure for Examples 52–53.

A mixture of phenol intermediate I-14 (0.05 mmol.), isocyanate (0.05mmol), cesium hydrogen carbonate (0.5 mg) and tetrahydrofuran (0.5 mL)was stirred at room temperature for 1 day. The solvent was evaporatedand the residue stirred for 8 hours with ethyl acetate and 3N HCl. Theethyl acetate was removed by evaporation and the aqueous solution wasdecanted from the solid. The residue was triturated with methanol andthe product collected.

Example 52

(79%) MS m/e 546 (M+1); ¹H NMR (DMSO-d₆) 11.60 (s, 1H), 8.34 (s, 1H),8.16 (d, 1H), 7.80 (t, 1H), 7.59 (s, 1H), 7.52 (d, 1H), 7.34 (m, H),7.26 (m, H), 7.19 (m, H), 4.76 (s, 2H), 4.68 (m, 1H), 3.00 (m, 2H), 2.83(t, 4H), 2.66 (t, 2H), 1.31 (d, 6H).

Example 53

MS m/e 511 (M+1); ¹H NMR (DMSO-d₆) 11.61 (s, 1H), 8.33 (s, 1H), 8.30 (t,1H), 8.16 (d, 1H), 7.67 (s, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.33 (d,2H), 7.19 (d, 2H), 6.86 (s, 1H), 6.78 (d, 1H), 4.77 (s, 2H), 4.69 (m,1H), 4.28 (d, 2H), 4.18 (d, 1H), 3.00 (t, 2H), 2.82 (t, 2H), 1.31 (d,6H).

Synthesis of amine intermediate I-15: To a stirred suspension ofbromo-intermediate I-8 (2.44 g, 6.27 mmol) in benzene (180 mL)/NMP (15mL) was added p-toluenesulfonic acid (1.19 g, 6.27 mmol) and4,4′-dimethoxybenzhydrol (1.84 g, 7.5 mmol). The reaction mixture washeated to reflux for 18 h then cooled to room temperature. The reactionsolvent was removed in vacuo. The solid was dissolved in ethyl acetateand washed with sodium bicarbonate, water and brine. The organic phasewas dried over magnesium sulfate, filtered and concentrated in vacuo togive the product (4.44 g). The product (2.28 g, 3.7 mmol) was placed ina schlenk tube along with dichlorobistriphenylphosphine palladium (210mg, 0.3 mmol), triethylamine (1 mL) and 2-methoxyethanol (100 mL).Carbon monoxide was added and the tube was sealed and heated to 150° C.After 4 h, additional carbon monoxide was added and the mixturecontinued to be heated. This was repeated one more time. After a totalreaction time of 24 h, the mixture was cooled to room temperature andfiltered through celite. The celite was washed with THF and the filtrateconcentrated in vacuo. The solid was purified by flash chromatography onsilica gel to give product.

Preparation of acid: To a stirred solution of ester (1 equiv.) at roomtemperature was added lithium hydroxide (3 equiv.) in one portion. Thereaction mixture was heated to 60° C. for 48 h. The mixture was cooledto room temperature, diluted with ethyl acetate, and washed with 10% HCland water. The organic phase was dried over magnesium sulfate, filteredand concentrated in vacuo to product. MS (ESI): m/e 687 (M+1)⁺. To astirred solution of acid (1 equiv.) in benzene was added triethylamine(1.96 equiv.) followed by diphenylphosphoryl azide (2 equiv.). Thereaction mixture was heated to reflux for 3 h. The amine (2 mL) wasadded and the mixture cooled to room temperature. The reaction solventwas removed in vacuo leaving an oil. The material was purified bypreparative plate chromatography on silica gel using 5%methanol/chloroform to give I-16. Debenzylation was accomplished usingpalladium hydroxide in methanol with catalytic concentrated HCl under 50psi hydrogen for 48–96 h to give intermediate I-15.

Examples 54–58 were prepared using intermediates I-15 or I-16.

Example 54

(71% yield) ¹H NMR (DMSO-d₆): δ 1.2–1.35 (m, 5H), 1.57 (m, 1H), 1.73 (m,2H), 1.86 (,. 2H), 2.82 (m, 2H), 3.50 (m, 2H), 3.84 (m, 5H), 4.64 (m,2H), 4.73 (s, 2H), 6.06 (m, 1H), 6.80 (d, 1H), 6.89 (s, 1H), 7.41 (d,1H), 7.58 (d, 1H), 7.91 (d, 1H), 8.08 (s, 1H), 8.32 (d, 2H).

Example 55

(92% yield) ¹H NMR (DMSO-d₆): δ 2.75 (m, 2H), 3.30 (m, 2H), 3.75 (s,6H), 3.80 (m, 2H), 3.81 (s, 3H), 4.30 (d, 2H), 4.35 (s, 2H), 4.62 (s,2H), 4.78 (m, 2H), 6.26 (s, 1H), 3.39 (s, 1H), 6.49 (t, 1H), 6.69 (s,1H), 6.82 (d, 1H), 6.90 (s, 1H), 6.95 (d, 4H), 7.01 (m, 2H), 7.14 (d,3H), 7.19 (d, 4H), 7.58 (m, 2H), 7.73 (s, 1H), 7.90 (d, 1H), 8.48 (s,1H).

Example 56

MS (ESI) m/e 630 (M+1)⁺.

Example 57

(52% yield) ¹H NMR (DMSO-d): δ 2.75 (m, 2H), 3.74 (s, 6H), 3.29 (m, 2H),3.82 (s, 5H), 3.84 (m, 2H), 4.36 (s, 2H), 4.65 (s, 2H), 4.83 (m, 2H),6.70 (s, 1H), 6.84 (d, 1H), 6.91 (s, 1H), 6.96 (d, 4H), 7.01 (m, 2H),7.15 (m, 4H), 7.22 (d, 4H), 7.32 (s, 1H), 7.67 (s, 1H), 7.70 (d, 1H),7.80 (d, 1H), 7.91 (d, 1H), 8.04 (s, 1H), 10.1 (s, 1H).

Example 58

light gray-brown solid (51% yield). ¹H NMR (DMSO-d₆): δ 1.09 (t, 6H),2.79 (m, 2H), 3.40 (m, 2H), 3.70 (m, 2H), 3.82 (s, 3H), 4.60 (m, 2H),4.73 (s, 2H), 5.75 (s, 2H), 6.80 (d, 1H), 6.89 (s, 1H), 7.59 (d, 2H),7.89 (d, 1H), 8.15 (s, 1H), 8.32 (s, 1H); MS (ESI): m/e 500 (M+1)⁺.

Example 59

A mixture of intermediate I-17 (46.3 mg, 0.1 mmol),Pd(dibenzylideneacetone)₂ (2.87 mg, 0.005 mmol), P(t-Bu)₃ (9.9 uL, 0.04mmol), sodium t-butoxide (14.4 mg, 0.15 mmol) and pyrrolidine (13 uL,0.15 mmol) in 2.0 mL of xylene was refluxed under argon for 72 hour. Thereaction was monitored by HPLC. The reaction was diluted with CH₂Cl₂,filtered through celite and washed with CH₂Cl₂. The solvent wasconcentration and the product purified by flash chromatography using 70%EtOAc in hexane to provided 7.5 mg (17%) of the6-cyano-8-fluoro-2-pyrrolidin-1-yl-12,13-dihydro-11H-11-aza-indeno[2,1-a]phenanthrene-5-carboxylicacid ethyl ester. MS: 452 m/e (M−H)⁻. A mixture of cyanoesterintermediate (6 mg, 0.013 mmol), Raney-Ni (20 mg) in 1.5 mL of DMF and0.15 mL of MeOH was hydrogenated under 50 psi H₂ on a Parr apparatus for1 week at room temperature. The reaction was monitored by HPLC. Thecatalyst was removed by filtration and the solvent concentrated toafford 3.5 mg (66%) of the product lactam. MS m/e 412 (M+1)⁺.

Example 60

A mixture of intermediate I-14 (16.5 mg, 0.041 mmol) and cesiumcarbonate (88 mg, 1.1 eq) in 2.0 mL of CH₃CN was added cyclopentylbromide (8.0 uL, 2.0 eq.) under N₂. After stirred at 70° C. for 24hours, the mixture was diluted with CH₂Cl₂ and filtered through celiteand concentrated. Purification by preparative TLC plate with CH₂Cl₂/MeOHafforded the product (4.0 mg, 23%); MS: 467 m/e (M+1)⁺.

General Methods for Synthesis of Examples 61–67.

Method A: To a mixture of hydroxy intermediate (0.2 mmol), potassiumiodide (3.3 mg, 0.1 eq.), N-tetrabutylammonium bromide (0.1 eq), cesiumhydroxide hydrate (3 eq) and 20 mg of 4 Å sieves in 2.0 mL of CH₃CN wasadded the appropriate alkyl bromide or alkyl iodide under N₂. After themixture was stirred at 50° C. for 14–72 hours, the reaction mixture wasdiluted with CH₃CN and filtered through celite and concentrated. Theresidue was diluted with CH₂Cl₂ and washed with water and dried overmagnesium sulfate. Purification by preparative TLC plate orcrystallization with CH₂Cl₂/MeOH afforded the desired products.

Method B: To a mixture of hydroxy intermediate (0.2 mmol) and cesiumcarbonate (3 eq) in 2.0 mL of CH₃CN was added the appropriate alkylbromide or iodide under N₂. After the mixture was stirred at 50–80° C.for 14–72 hours, the mixture was diluted with CH₃CN, filtered throughcelite and concentrated. The residue was diluted with CH₂Cl₂ and washedwith water and dried over magnesium sulfate. Purification by preparativeTLC plate or crystallization with CH₂Cl₂/MeOH afforded the desiredproduct.

Method C: To a mixture of hydroxy intermediate (0.1 mmol), sodiumhydroxide (1.5 eq.) and N-tetrabutylammonium bromide (0.1 eq) in 0.5 mLof CH₂Cl₂ and 0.5 mL of water was added the appropriate alkyl bromideunder N₂. After the mixture was stirred at room temperature for 14–72hours, the reaction mixture was concentrated and the residue was washedwith water and dried over magnesium sulfate. Purification by preparativeTLC plate with CH₂Cl₂/MeOH or crystallization afforded the desiredproduct.

Example 61

Method A; phenol I-18 and cyclopentyl bromide; 14 hr; preparative TLC(10% MeOH in CH₂Cl₂); yield 10%; MS: m/e 453 m/e (M+1)⁺.

Example 62

Method A; phenol I-18 and cyclohexyl iodide; 40 hr; preparative TLC (10%MeOH in CH₂Cl₂); yield 10%; MS: m/e 467 m/e (M+1)⁺.

Example 63

Method B; phenol I-18 and 3-bromocyclohexene; 48 hr at 80° C.;preparative TLC (10% MeOH in CH₂Cl₂); yield 19%; MS: m/e 487 m/e(M+Na)⁺.

Example 64

Method A phenol I-18 and dimethyl bromomalonate; 48 hr at 80° C.;preparative TLC (10% MeOH in CH₂Cl₂); yield 18%; MS: m/e 537 m/e(M+Na)⁺.

Example 65

Method A; phenol I-18 and 4-bromo-1,7-diethoxy-heptane; 24 hr at 80° C.;preparative TLC (10% MeOH in CH₂Cl₂); yield 3%; MS: m/e 571 m/e (M+1)⁺.

Example 66 and Example 67

Method A; phenol I-19 and cyclopentyl bromide; 20 hr at 50° C.;preparative TLC (10% MeOH in CH₂Cl₂); yield Example 66 (5%); MS: 499 m/e(M+Na)⁺; Example 67 (20%); MS 431 m/e (M+Na)⁺.

Example 68

To a stirred suspension of aluminum chloride (0.35 g, 0.0026 mol) inmethylene chloride (8 mL) under nitrogen was added3-carbomethoxypropionyl chloride (0.323 mL, 0.0026 mol). The mixturegradually became homogeneous and a suspension of intermediate I-13 (0.32g, 0.00087 mol) in 1,2-dichloroethane (4 mL) was added. The mixture washeated to reflux overnight. Additional acylating agent (1 equiv.) wasprepared and added to the reaction mixture. After heating an additional3 h, the mixture was cooled to room temperature. The reaction mixturewas poured over ice, concentrated HCl was added along with additionalmethylene chloride. The mixture was stirred for 30 minutes thenextracted with methylene chloride, dried over magnesium sulfate, andconcentrated in vacuo to give a tan solid (0.41 g, 78% yield). To astirred solution of the above compound (100 mg, 0.167 mmol) in THF/H₂O(4 mL, 3:1) was added sodium borohydride (12.6 mg, 0.334 mmol) in oneportion. The mixture was stirred at room temperature overnight. Thereaction solvent was removed and additional water was added to theflask. The resulting precipitate was collected by filtration. Furtherpurification was accomplished using preparative plate chromatography onsilica gel using 5% methanol/chloroform as the developing solventyielding a white solid (52 mg, 52% yield). MS (ESI): m/e 599 (M+1)⁺. Toa stirred solution of the previous product (25 mg, 0.0418 mmol) in THF(6 mL) under nitrogen was added sodium hydride (5 mg, 0.125 mmol) in oneportion. The mixture was stirred at 0° C. initially then was warmed toroom temperature. The yellow reaction mixture was diluted withdichloromethane and washed with water. The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo to a light yellowsolid. The solid was purified by preparative plate chromatographydeveloped in 5% methanol/chloroform (12.6 mg, 53% yield). ¹H NMR(CDCl₃): δ 0.93 (m, 2H), 2.16 (m, 2H), 2.38 (m, 1H), 2.64 (s, 5H), 2.77(m, 3H),2.79 (m, 2H), 3.71 (s, 3H), 4.01 (s, 2H), 4.15 (m, 2H), 4.46 (s,2H), 4.52 (m, 2H), 5.72 (m, 1H), 7.36 (t, 1H), 7.49 (m, 4H), 7.62 (s,1H), 9.43 (broad s, 1H); MS (ESI): m/e 567 (M+1)⁺.

Example 69

To a suspension of aluminum chloride (0.17 g, 1.24 mmol) in1,2-dichloroethane (5 mL) was added 2,2-dimethylsuccinic anhydride (0.16g, 1.98 mmol). The mixture was stirred for 20 min. and a suspension ofintermediate I-4 (0.22 g, 9.88 mmol) in 1,2-dichloroethane (4 mL) wasadded. The mixture was heated to 70° C. in an oil bath overnight.Additional acylating agent (2 equiv.) was added and the continued to beheated for 1 h. The reaction mixture was cooled to room temperature andpoured over ice. Concentrated HCl (2 mL) was added and a precipitateformed. The solid was collected by filtration to give a tan solid (0.25g, 85% yield). MS (ESI): m/e 483 (M+1)⁺. To a stirred solution of theprevious product (183 mg, 0.38 mmol) in THF (2 mL)/methanol (1 mL) atroom temperature under nitrogen was added trimethylsilyldiazomethanedropwise (0.5 mL). The reaction mixture became cloudy and vigorousevolution of gas was observed. The mixture was stirred at roomtemperature for 1 h. The reaction solvent was removed in vacuo leaving ayellow film. The film was triturated with methylene chloride/methanoland the solid collected by filtration. The solid was purified bypreparative plate chromatography on silica gel to give a pale yellowsolid (180 mg, 96% yield). MS (ESI): m/e 497 (M+1)⁺. To a stirredsolution of the previous product (180 mg, 0.362 mmol) in THF (5 mL)under nitrogen was added lithium borohydride (1.45 mL, 1.45 mmol)dropwise. The mixture stirred at room temperature for 4 h. The mixturewas cooled and quenched with water. Vigorous evolution of gas wasobserved. After stirring at room temperature for 1 h, the reactionsolvent was removed in vacuo leaving a white solid which was trituratedwith water. The solid was collected by filtration and purified bypreparative plate chromatography on silica gel using 10%methanol/chloroform to give a tan solid (90.3 mg, 53% yield). MS (ESI):m/e 471 (M+1)⁺. To a stirred suspension of the previous product (40 mg,0.085 mmol) in methylene chloride (5 mL) at room temperature undernitrogen was added trifluoroacetic acid (6.5 μl, 0.085 mmol) dropwise.The mixture was stirred at room temperature for 4 h. The reactionsolvent was removed in vacuo leaving a tan-brown solid which waspurified by preparative plate chromatography on silica gel using 5%methanol/chloroform to give a tan solid (28 mg, 74% yield). ¹H NMR(DMSO-d₆): δ 1.19 (d, 6H), 1.73 (t, 1H), 2.18 (m, 1H), 2.84 (m, 2H),3.01 (m, 2H), 3.59 (d, 1H), 3.75 (d, 1H), 3.82 (s, 3H), 4.79 (s, 2H),5.16 (m, 1H), 6.82 (d, 1H), 6.89 (s, 1H), 7.44 (d, 1H), 7.53 (d, 1H),7.87 (s, 1H), 8.19 (d, 1H), 8.33 (s, 1H), 11.56 (s, 1H); MS (ESI): m/e453 (M+1)⁺.

Example 70

This compound was prepared using the general procedure of Example 68. Toa stirred solution of the acyl intermediate from Example 69 (0.15 g,0.31 mmol) in THF/H₂O (3:1, 8 mL) under nitrogen was added sodiumborohydride (47 mg, 1.24 mmol) in one portion. An oily precipitateformed on the walls of the flask. The mixture was stirred at roomtemperature overnight. The reaction mixture was cooled to 0° C. in anice bath and methanol was added slowly to quench the reaction. Thereaction solvent was removed in vacuo leaving a white solid that wascollected by filtration and purified by preparative plate chromatographyon silica gel using 10% methanol/chloroform to give the product (25 mg,17% yield). ¹H NMR (DMSO-d₆): δ 1.30 (s, 3H), 1.34 (s, 3H), 2.27 (t,2H), 2.85 (m, 2H), 3.02 (m, 2H), 3.82 (s, 3H), 4.82 (s, 2H), 5.77 (m,1H), 6.82 (d, 1H), 6.90 (s, 1H), 7.53 (d, 1H), 7.60 (d, 1H), 8.02 (s,1H), 8.20 (s, 1H), 8.44 (s, 1H), 11.69 (s, 1H); MS (ESI): m/e 467(M+1)⁺.

Example 71

This compound was prepared using the general procedure of Example 70.The acylated product was prepared (70 mg, 0.141 mmol) and suspended inTHF/H₂O (8 mL, 3:1) and cooled to 0° C. Sodium borohydride (16 mg, 0.423mmol) was added to the reaction mixture in one portion. Vigorousevolution of gas was observed. The mixture was warmed to roomtemperature overnight. The mixture was extracted with ethyl acetate,dried over magnesium sulfate, filtered, and concentrated in vacuo to awhite solid. The solid was purified by preparative plate chromatographyon silica gel using 5% methanol/chloroform to give an off-white solid(12 mg, 18% yield). ¹H NMR (DMSO-d₆): δ 2.37 (m, 2H), 2.64–2.80 (m, 4H),2.84 (m, 2H), 3.02 (m, 2H), 3.82 (s, 3H), 4.71 (m, 2H), 4.82 (s, 2H),5.71 (t, 1H), 6.82 (d, 1H), 6.90 (s, 1H), 7.50 (d, 1H), 7.60 (d, 1H),7.99 (s, 1H), 8.20 (d, 1H), 8.38 (s, 1H), 11.7 (s, 1H); MS (ESI): m/e439 (M+1)⁺.

Example 72

This compound was prepared using the general procedure for Example 70using 3,3-dimethyl glutaric anhydride. MS (ESI): m/e 481(M+1)⁺.

Example 73

Prepared by reaction of Example 72 with ethyl iodide and cesiumcarbonate in acetonitrile. MS (ESI): m/e 509(M+1)⁺.

Example 74

This compound was prepared using the general procedure for Example 70.MS (ESI): m/e 495 (M+1)⁺.

Example 75

Following the procedure for Example 9, step A, the acylated product wasprepared (100 mg, 0.201 mmol) and suspended in THF (4 mL) at roomtemperature under nitrogen. Lithium borohydride (0.4 mL, 0.806 mmol, 2 Msolution) was added dropwise to the reaction mixture. After stirring atroom temperature for 4 h, the mixture was cooled to 0° C. in an ice bathand water was added slowly dropwise to quench the reaction. Evolution ofgas was observed and the mixture gradually became homogeneous. Thereaction solvent was removed in vacuo leaving a white solid which wastriturated with water and the resulting precipitate was collected byfiltration to give an off-white solid (86 mg, 97% yield). MS (ESI): m/e443 (M+1)⁺. To a stirred suspension of the previously prepared diol (80mg, 0.181 mmol) in 1,2 dichloroethane (4 mL) was added trifluoroaceticanhydride (25.5 μl, 0.181 mmol) dropwise. The mixture became homogeneousand was heated in a sealed tube at 70° C. overnight. The mixture wascooled to room temperature and the solvent removed in vacuo leaving adark solid. The solid was triturated with ether and collected byfiltration. The solid was purified by preparative plate chromatographyon silica gel using 5% methanol/chloroform to give an tan solid (12 mg,16% yield). ¹H NMR (DMSO-d₆): δ 1.83 (m, 1H), 2.02 (m, 2H), 2.35 (m,1H), 2.86 (m, 2H), 3.03 (m, 2H), 3.83 (s, 3H), 3.86 (m, 1H), 4.07 (m,1H), 4.81 (s, 2H), 4.97 (t, 1H), 6.82 (d, 1H), 6.90 (s, 1H), 7.44 (d,1H), 7.53 (d, 1H), 7.87 (s, 1H), 8.19 (d, 1H), 8.33 (s, 1H), 11.56 (s,1H); MS (ESI): m/e 425 (M+1)⁺.

Example 76

The compound was prepared using the same method as Example 75 usingintermediate I-13 and methyl-5-chloro-5-oxovalerate. The product wasisolated as an off-white solid (17.4 mg, 32% yield). ¹H NMR (DMSO-d₆)4.76 (m, 2H), 4.93 (s, 2H), 7.35–7.45 (m, 2H), 7.53 (m, 1H), 7.68 (t,2H), 7.90 (s, 1H), 8.53 (s, 1H), 9.51 (d, 1H); MS (ESI): m/e 453 (M+1)⁺.

Example 77

The compound was prepared using the same method as Example 75 usingintermediate I-13 and 3-carbomethoxypropionyl chloride to give anoff-white solid (8.2 mg, 11%). ¹H NMR (DMSO-d₆): δ 2.01 (m, 4H), 2.41(m, 2H), 3.51 (m, 2H), 3.90 (m, 1H), 4.08 (m, 2H), 4.56 (s, 2H), 4.75(m, 2H), 4.95 (s, 2H), 4.98 (m, 1H), 7.35 (m, 1H), 7.43 (m, 1H), 7.51(d, 1H), 7.70 (m, 2H), 7.90 (s, 1H), 8.54 (s, 1H), 9.50 (d, 1H); MS(ESI): m/e 439 (M+1)⁺.

Example 78

To a stirred suspension of aluminum chloride (0.57 g, 4.3 mmol) in1,2-dichloroethane (6 mL) was added carbomethoxypropionyl chloride(0.529 mL, 4.3 mmol). The reaction mixture became homogeneous and asuspension of intermediate I-40 (0.61 g, 1.72 mol) in 1,2-dichloroethane(4 mL) was added to the reaction mixture. The heterogeneous orangemixture was heated to 60° C. in an oil bath overnight. The mixture waspoured over ice and concentrated HCl (2 mL) was added. The mixture wasstirred at room temperature for 30 minutes then the resulting solidcollected by filtration and air-dried overnight. The solid was slurriedin methanol/methylene chloride and collected by filtration to give a tansolid (0.53 g, 73% yield). MS (ESI): m/e 425 (M+1)⁺. To a suspension ofthe above product (260 mg, 0.613 mmol) in THF (5 mL) under nitrogen wasadded lithium borohydride (1.23 mL, 2M in THF) dropwise and vigorousevolution of gas was observed. When all of the starting material hadbeen consumed by HPLC, the reaction mixture was cooled to 0° C. in anice bath and water was added very slowly. Vigorous evolution of gas wasobserved. After the evolution of gas subsided, the reaction mixturebecame homogeneous. The reaction solvent was removed in vacuo andadditional water was added. The precipitate was collected by filtrationyielding a tan solid (0.18 g, 75% yield). MS (ESI): m/e 399 (M+1)⁺, 381(M−H₂O)⁺. To a suspension of the previous compound (43 mg, 0.108 mmol)in methylene chloride (2.5 mL) in a glass tube was added trifluoroaceticanhydride (15.2 μL, 0.108 mmol). The tube was sealed and heated to 80°C. in an oil bath overnight. The reaction was cooled to room temperatureand the solvent removed in vacuo leaving a gray solid. The solid wastriturated with ether, collected by filtration and purified bypreparative plate chromatography on silica gel developed with 5%methanol/chloroform to give a tan solid (26 mg, 63% yield). ¹H NMR(DMSO-d₆): δ 1.86 (m, 1H), 2.02 (m, 2H), 2.36 (m, 1H), 3.85 (dd, 1H),4.08 (dd, 1H), 4.17 (s, 2H), 4.94 (s, 2H), 5.0 (m, 1H) 7.34 (m, 1H),7.36–7.56 (m, 2H), 7.57 (d, 1H), 7.68 (d, 1H), 7.90 (s, 1H), 8.50 (s,1H), 9.39 (d, 1H), 11.87 (s, 1H); MS (ESI): m/e 381 (M+1)⁺

Example 79

The compound was prepared using the same method as Example 78 withmethyl 4-chloro-4-oxobutyrate as the acid chloride. The product wasisolated as a tan-yellow solid (36 mg, 34% yield). ¹H NMR (DMSO-d₆): δ1.65 (m, 4H), 1.91 (m, 2H), 3.60 (m, 1H), 4.08 (d, 1H), 4.17 (s, 2H),4.50 (d, 1H), 4.94 (s, 2H), 7.34 (t, 1H), 7.40–7.47 (m, 2H), 7.56 (d,1H), 7.68 (d, 1H), 7.90 (s, 1H), 8.50 (s, 1H), 9.39 (d, 1H), 11.86 (s,1H); MS (ESI): m/e 395 (M+1)⁺.

Example 80

To a suspension of aluminum chloride (0.27 g, 2.01 mmol) in1,2-dichloroethane (5 mL) at room temperature under nitrogen was addedmethyl-5-chloro-5-oxovalerate (0.28 mL, 2.01 mmol) dropwise. Thesuspension gradually became homogeneous and was stirred for 30 minutes.A suspension of intermediate I-4 (0.31 g, 0.875 mmol) in1,2-dichloroethane (3 mL) was added to the reaction mixture and thenheated to reflux overnight. The mixture was cooled to room temperatureand poured over ice. Concentrated HCl (2 mL) was added and the mixturewas stirred for 30 min. The resulting precipitate was collected byfiltration and dried in vacuo to give a light orange solid (37 g, 88%yield). MS (ESI): m/e 483 (M+1)⁺. To a stirred suspension of theprevious product (240 mg, 0.498 mmol) in THF (8 mL) under nitrogen wasadded lithium borohydride (1.48 mL, 2.97 mmol, 2M soln). Evolution ofgas was observed and the mixture stirred at room temperature for 4 h.The mixture was cooled to 0° C. and quenched carefully with water. Afterstirring at room temperature for 1 h, the reaction solvent was removedin vacuo. The resulting solid was triturated with water and collected byfiltration to give a white solid (0.21 g, 91% yield). MS (ESI): m/e 457(M+1)⁺. To a stirred suspension of the previous product (77 mg, 0.168mmol) in 1,2-dichloroethane (3 mL) at 0° C. under nitrogen was addedtrifluoroacetic acid (23.9 μl, 0.169 mmol). The reaction mixture wasstirred at 0° C. for 1 h then warmed to room temperature for 5 h. Thereaction solvent was removed in vacuo leaving a tan solid which waspurified by preparative plate chromatography on silica gel using 10%methanol/chloroform to give a tan solid (46.7 mg, 63% yield). ¹H NMR(DMSO-d₆): δ 1.59–1.67 (m, 4H), 1.91 (m, 2H), 2.84 (m, 2H), 3.00 (m,2H), 3.60 (t, 1H), 4.07 (d, 1H), 4.48 (d, 1H), 4.79 (s, 2H), 6.82 (d,1H), 6.90 (s, 1H), 7.43 (d, 1H), 7.51 (d, 1H), 7.86 (s, 1H), 8.19 (d,1H), 8.33 (s, 1H), 11.5 (s, 1H); MS (ESI): m/e 439 (M+1)⁺.

Example 81

To a stirred suspension of aluminum chloride (0.36 g, 2.69 mmol) in1,2-dichloroethane (10 mL) under nitrogen was added3-(carbomethoxy)propionyl chloride (0.33 mL, 2.69 mmol) dropwise. Themixture was stirred at room temperature for 30 min. Intermediate I-41(0.43 g, 1.08 mmol) was added and the mixture stirred at roomtemperature for 1 h then warmed to 60° C. overnight. Additionalacylating reagent (2 equiv.) was added and the reaction mixturecontinued to stir at 60° C. overnight. The mixture was cooled to roomtemperature, poured over ice and concentrated HCl was added. The mixturewas stirred for 1 h and the precipitate collected by filtration beingwashed several times with water. The solid was purified by preparativeplate chromatography on silica gel using 5% methanol/chloroform to givethe product (0.58 g, 85% yield). MS (ESI): m/e 627 (M+1)⁺. To a stirredsolution of the previous product (0.39 g, 0.622 mmol) in THF (10 mL) atroom temperature under nitrogen was added lithium borohydride (4.9 mL,4.98 mmol, 1.0 M solution) dropwise. Vigorous evolution of gas wasobserved and a precipitate began to form. The reaction mixture wascooled to 0° C. and water was carefully added. Following the subsidingof evolution of gas, the reaction solvent was removed in vacuo to give awhite solid. The solid was triturated with water and collected byfiltration to give an off-white solid (0.23 g, 93% yield). MS (ESI): m/e487 (M+1)⁺. To a suspension of the previous product (130 mg, 0.267 mmol)in 1,2-dichloroethane (4 mL) in a glass tube was added trifluoroaceticacid (37.3 μl, 0.267 mmol) at room temperature. The reaction mixture wasstirred for 30 min. at room temperature then heated to reflux for 1 h.The mixture was cooled to room temperature and the solvent removed invacuo leaving a grayish-white solid. The solid was purified bypreparative plate chromatography on silica gel using 5%methanol/chloroform to give an off-white solid (60.9 mg, 49% yield). ¹HNMR (DMSO-d₆): δ 1.79–1.86 (m, 1H), 2.02 (m, 2H), 2.36 (m, 1H), 2.79 (m,2H), 3.82 (s, 3H), 3.86 (m, 2H), 4.08 (q, 1H), 4.64 (t, 2H), 4.30 (s,2H), 5.00 (t, 2H), 6.81 (d, 1H), 6.90 (s, 1H), 7.46 (d, 1H), 7.64 (d,1H), 7.84 (s, 1H), 7.88 (d, 1H), 8.36 (s, 1H); MS (ESI): m/e 469 (M+1)⁺.

Example 82

This compound was prepared by the same general procedure as Example 81and methyl-5-chloro-5-oxovalerate. The product was isolated as anoff-white solid (85 mg, 80% yield). ¹H NMR (DMSO-d₆): δ 1.59–1.66 (m,4H), 1.91 (m, 2H), 2.79 (m, 2H), 3.60 (t, 1H), 3.82 (s, 5H), 4.08 (d,1H), 4.50 (d, 1H), 4.63 (t, 2H), 4.79 (s, 2H), 4.98 (t, 1H), 6.80 (d,1H), 6.90 (s, 1H), 7.47 (d, 1H), 7.63 (d, 1H), 7.84 (s, 1H), 7.88 (d,1H), 8.36 (s, 1H); MS (ESI): m/e 483 (M+1)⁺, 505 (M+Na)⁺.

Example 83

To a stirred suspension of Example 80 (52 mg, 0.119 mmol) inacetonitrile (5 mL) at room temperature under nitrogen was added cesiumcarbonate (193 mg, 0.593 mmol) followed by ethyl bromide (44.3 μl, 0.593mmol). The reaction mixture was heated in a sealed tube at 100° C. for 1h. The mixture was cooled to room temperature, diluted with methylenechloride and washed with water. The organic phase was dried overmagnesium sulfate, filtered and concentrated in vacuo to a yellow film.The film was triturated with ether and the solid collected byfiltration. The solid was purified by preparative plate chromatographyon silica gel using 10% methanol/chloroform to give a light-yellow solid(25 mg, 45% yield). ¹H NMR (DMSO-d₆) δ 1.38 (t, 3H), 1.53–1.77 (m, 4H),1.91 (m, 2H), 2.81 (m, 2H), 3.38 (m, 1H), 3.82 (s, 3H), 4.08 (d, 1H),4.50 (d, 1H), 4.60 (m, 2H), 4.79 (s, 2H), 6.81 (d, 1H), 6.90 (s, 1H),7.49 (d, 1H), 7.62 (d, 1H), 7.85 (s, 1H), 7.90 (d, 1H), 8.37 (s, 1H); MS(ESI): m/e 467 (M+1)⁺.

Examples 84 and Example 85

The enantiomers of Example 83 were separated by chiral HPLC using aChiralpak AD column 4.6×250 mm with a flow rate of 0.5 mL/min. withethanol as solvent. Example 84 eluted with a R_(t) of 19.1 minutes MS(ESI): m/e 467 (M+1)⁺. Example 85 eluted with a R_(t) of 24.7 minutes MS(ESI): m/e 467 (M+1)⁺.

Examples 86–91 were prepared using the general procedure for Example 69using the appropriate cyclic anhydride.

Example 86

MS (ESI): m/e 423 (M+1)⁺.

Example 87

MS (ESI): m/e 481 (M+1)⁺.

Example 88

MS (ESI): m/e 481 (M+1)⁺.

Example 89

MS (ESI): m/e 507 (M+1)⁺.

Example 90

MS (ESI): m/e 467 (M+1)⁺.

Example 91

MS (ESI): m/e 423 (M+1)⁺.

Examples 92–99 were prepared from Example 86 using the method of Example83.

Example 92

MS (ESI): m/e 451 (M+1)⁺.

Example 93

MS (ESI): m/e 465 (M+1)⁺.

Example 94

MS (ESI): m/e 437 (M+1)⁺.

Example 95

MS (ESI): m/e 493 (M+1)⁺.

Example 96

MS (ESI): m/e 463 (M+1)⁺.

Example 97

MS (ESI): m/e 507 (M+1)⁺.

Example 98

MS (ESI): m/e 479 (M+1)⁺.

Example 99

MS (ESI): m/e 522 (M+1)⁺.

Examples 100–103 were prepared from intermediate I-4 and the appropriatecyclic anhydride using the general procedure for Example 69.

Example 100

MS (ESI): m/e 493 (M+1)⁺.

Example 101

MS (ESI): m/e 481 (M+1)⁺.

Example 102

MS (ESI): m/e 467 (M+1)⁺.

Example 103

MS (ESI): m/e 467 (M+1)⁺.

Examples 104–123 were prepared from Example 80 and the appropriatebromide or iodide using the method for Example 83.

Example 104

MS (ESI): m/e 495 (M+1)⁺

Example 105

MS (ESI): m/e 453 (M+1)⁺

Example 106

MS (ESI): m/e 509 (M+1)⁺.

Example 107

MS (ESI): m/e 523 (M+1)⁺.

Example 108

MS (ESI): m/e 495 (M+1)⁺.

Example 109

MS (ESI): m/e 509 (M+1)⁺.

Example 110

MS (ESI): m/e 479 (M+1)⁺.

Example 111

MS (ESI): m/e 611 (M+1)⁺.

Example 112

MS (ESI): m/e 581 (M+1)⁺.

Example 113

MS (ESI): m/e 497 (M+1)⁺.

Example 114

MS (ESI): m/e 538 (M+1)⁺.

Example 115

MS (ESI): m/e 552 (M+1)⁺.

Example 116

MS (ESI): m/e 665 (M+1)⁺.

Example 117

MS (ESI): m/e 507 (M+1)⁺.

Example 118

MS (ESI): m/e 506 (M+1)⁺.

Example 119

MS (ESI): m/e 481 (M+1)⁺.

Example 120

MS (ESI): m/e 495 (M+1)⁺.

Example 121

MS (ESI): m/e 483 (M+1)⁺.

Example 122

MS (ESI): m/e 493 (M+1)⁺.

Example 123

MS (ESI): m/e 507 (M+1)⁺.

Examples 124–133 were prepared by reacting Example 103 with theappropriate bromide or iodide using the method of Example 80.

Example 124

MS (ESI): m/e 639 (M+1)⁺

Example 125

MS (ESI): m/e 525 (M+1)⁺.

Example 126

MS (ESI): m/e 509 (M+1)⁺.

Example 127

MS (ESI): m/e 625 (M+1)⁺.

Example 128

MS (ESI): m/e 511 (M+1)⁺.

Example 129

MS (ESI): m/e 495 (M+1)⁺.

Example 130

MS (ESI): m/e 534 (M+1)⁺.

Example 131

MS (ESI): m/e 481 (M+1)⁺.

Example 132

MS (ESI): m/e 521 (M+1)⁺.

Example 133

MS (ESI): m/e 505 (M+1)⁺.

Example 134

The phenol intermediate I-19 under Friedel Craft conditions as describedfor Example 80 formed the C-, O- bis-acylated adduct which was reducedto the diol using lithium borohydride in a similar manner as describedin Example 80. To a stirred suspension of diol intermediate (1.19 g,2.69 mmol) in CH₂Cl₂ (40 mL) was added TFA (0.21 mL, 2.69 mmol) undernitrogen. The reaction mixture was stirred for 2 hours then additionalTFA (2 equiv.) was added. The reaction solvent was removed in vacuoleaving an off-white solid that was triturated with ether and collectedby filtration. ¹H NMR (DMSO-d₆) δ 1.59–1.69 (m, 4H), 1.87–1.91 (m, 2H),2.78 (m, 2H), 2.97 (m, 2H), 3.59 (m, 1H), 4.07 (d, 1H), 4.48 (d, 1H),4.78 (s, 2H), 6.63 (d, 1H), 6.70 (s, 1H), 7.42 (d, 1H), 7.50 (d, 1H),7.85 (s, 1H), 8.06 (d, 1H), 8.31 (s, 1H), 9.44 (s, 1H), 11.51 (s, 1H).

Example 135

Step 1. A solution of N-ethyl intermediate I-42 (510 mg, 1.24 mmol) indichloroethane (DCE) (15 ml) was added dropwise to a preformed solutionof AlCl₃ (1.37 g, 10.31 mmol) and methyl-4-(chloro-formyl)butyrate (1.42ml, 10.31 mmol) in DCE (10 ml) at room temperature. The reaction wasallowed to stir overnight at room temperature and ¹H NMR of a worked upand extracted aliquot showed conversion to product. To the stirringsolution was slowly added 10 ml of 2N HCl and the reaction allowed tostir at room temperature for 60 minutes. The resulting off white solidwas collected by vacuum filtration and washed with ether; 684 mg, 88%yield. MS (ESI): m/e 647 (M+Na)⁺.

Step 2. To a 0° C. solution of the product from Step 1 (684 mg, 1.24mmol) in 20 ml of anhydrous THF was added dropwise 6.20 ml (12.36 mmol)of a 2.0 M solution of LiBH₄ in THF. The reaction was allowed to stir atroom temperature for 60 hours and HPLC of an aliquot of the reactionshowed conversion to product. The reaction was evaporated to dryness andthe resulting white solid triturated in water and collected by vacuumfiltration and air dried; 540 mg, 93% yield. MS (ESI): m/e 477 (M+H)⁺.

Step 3. To a 0° C. solution of the product from Step 2 (530 mg, 1.13mmol) in 10 ml of anhydrous DCE was added 87 μl of trifluoroacetic aciddropwise with a syringe. The solution was allowed to warm to roomtemperature overnight. An HPLC of an aliquot of the reaction showedconversion to product. The reaction was evaporated to dryness and theresulting solid was triturated with ether and collected by vacuumfiltration; 611 mg, contains salts from reaction sequence, MS (ESI): m/e475 (M+Na)⁺.

General alkylation procedure for Examples 136–146: To a stirredsuspension of Example 134 in acetonitrile (0.04–0.06 mM) under nitrogenwas added the alkylating agent (3–5 equiv.) followed by cesium carbonate(3–5 equiv.). The mixture was heated to 50–80° C. overnight. Whencomplete, the reaction mixture was cooled to room temperature andconcentrated in vacuo to a solid. The solid was triturated with waterand collected by filtration. The products were purified by flash columnchromatography on silica gel, preparative silica gel plates orpreparative HPLC.

Example 136

white solid (14.3 mg, 37% yield). ¹H NMR (DMSO-d₆) δ 1.30 (d, 6H),1.60–1.67 (m, 4H), 1.87–1.90 (m, 2H), 2.90 (m, 2H), 3.00 (m, 2H), 3.59(m, 1H), 4.07 (d, 1H), 4.48 (d, 1H), 4.69 (m, 1H), 4.79 (s, 2H), 6.78(d, 1H), 6.87 (s, 1H), 7.43 (d, 1H), 7.51 (d, 1H), 7.86 (s, 1H), 8.16(d, 1H), 8.34 (s, 1H), 11.55 (s, 1H).

Example 137

(6.52 mg, 14% yield) MS (ESI): m/e 509 (M+H)⁺.

Example 138

(15.48 mg, 28% yield). MS (ESI): m/e 467 (M+H)⁺.

Example 139

(15.90 mg, 2.7% yield). MS (ESI): m/e 509 (M+H)⁺.

Example 140

(9.16 mg, 20% yield). MS (ESI): m/e 481 (M+H)⁺.

Example 141

(20.8 mg, 17% yield). MS (ESI): m/e 493 (M+H)⁺.

Example 142

(35 mg, 22% yield). ¹H NMR (DMSO-d₆): δ 0.34 (m, 2H), 0.58 (m, 2H), 1.26(m, 1H), 1.63 (m, 4H), 2.83 (m, 2H), 2.99 (m, 2H), 3.61 (m, 1H), 3.88(d, 2H), 4.07 (d, 1H), 4.48 (d, 1H), 4.79 (s, 2H), 6.79 (d, 1H), 6.89(s, 1H), 7.43 (d, 1H), 7.51 (d, 1H), 7.87 (s, 1H), 8.17 (d, 1H), 8.32(s, 1H).

Example 143

(27.17 mg, 41% yield). MS (ESI): m/e 581 (M+Na)⁺.

Example 144

MS (ESI): m/e 492 (M+1)⁺.

Example 145

MS (ESI): m/e 505 (M+1)⁺.

Example 146

MS (ESI): m/e 465 (M+1)⁺.

Example 147

MS (ESI): m/e 506 (M+1)⁺.

Example 148

MS (ESI): m/e 587 (M+1)⁺.

Using the general alkylation procedure described for Examples 136–143,Examples 149–158 were prepared from Example 136.

Example 149

(20.73 mg, 56% yield). MS (ESI) m/e 556 (M+Na)⁺.

Example 150

(12.04 mg, 26% yield). MS (ESI) m/e 517 (M+Na)⁺.

Example 151

(5.09 mg, 11% yield). MS (ESI) m/e 503 (M+Na)⁺.

Example 152

(6.94 mg, 13.7% yield). MS (ESI) m/e 545 (M+Na)⁺

Example 153

(10.5 mg, 21% yield). MS (ESI) m/e 521 (M+H)⁺.

Example 154

(19.1 mg, 11.7% yield). MS (ESI): m/e 517 (M+Na)⁺.

Example 155

MS (ESI): m/e 512 (M+1)⁺.

Example 156

MS (ESI): m/e 527 (M+1)⁺.

Example 157

MS (ESI): m/e 523 (M+1)⁺.

Example 158

MS (ESI): m/e 492 (M+1)⁺.

Example 159

This compound was prepared according to the procedure for Example 158where the phenol intermediate I-19 was acylated under Friedel Craftconditions with methyl 4-chloro-4-oxobutyrate and reduced with lithiumborohydride. To a stirred suspension of intermediate diol (0.39 g, 0.91mmol) in methylene chloride (15 mL) under nitrogen was added TFA (0.13mL, 0.91 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 4 h. The reaction solvent was removed in vacuo leaving awhite solid that was triturated with ether and collected by filtration(0.32 g, 86%). MS (ESI): m/e 441 (M+H)⁺, 463 (M+Na)⁺.

Using the general alkylation conditions described for Examples 136–143,Examples 160–165 were prepared from Example 159.

Example 160

(15.8 mg, 49%). ¹H NMR (DMSO-d₆): δ 1.84 (m, 1H), 2.01 (m, 2H), 2.36 (m,1H), 2.78 (m, 2H), 3.39 (m, 2H), 3.80 (s, 3H), 3.85 (m, 1H), 4.08 (m,1H), 4.13 (s, 3H), 4.79 (s, 2H), 4.98 (dd, 1H), 6.81 (d, 1H), 6.90 (s,1H), 7.48 (d, 1H), 7.62 (d, 1H), 7.85 (s, 1H), 7.92 (d, 1H), 8.37 (s,1H).

Example 161

(24.3 mg, 32%). ¹H NMR (DMSO-d₆): δ 1.35–1.4 (m, 6H), 1.83 (m, 1H), 2.01(m, 2H), 2.36 (m, 1H), 2.81 (m, 2H), 3.28 (m, 2H), 3.85 (m, 1H), 4.10(m, 3H), 4.61 (m, 2H), 4.79 (s, 2H), 4.98 (m, 1H), 6.79 (d, 1H), 6.89(s, 1H), 7.48 (d, 1H), 7.65 (d, 1H), 7.85 (s, 1H), 7.89 (d, 1H), 8.36(s, 1H).

Example 162

14.6 mg, 21%). MS (ESI): m/e 467 (M+H)⁺.

Example 163

(26 mg, 32%). MS (ESI): m/e 453 (M+H)⁺.

Example 164

This compound was prepared starting from Example 163 using the generalprocedure for Examples 148–155 (9.77 mg, 20%). MS (ESI) m/e 517 (M+Na)⁺.

Example 165

This compound was prepared by alkylation of Example 163 to give a yellowsolid (17.8 mg, 89%). MS (ESI): m/e 481 (M+H)⁺.

Example 166

This compound was prepared in step 3 in Example 100. The ketoester inTHF under nitrogen was reduced to the diol using lithium borohydride togive a solid which was collected purified by preparative platechromatography on silica gel using 10% methanol/chloroform to give a tansolid. MS (ESI): m/e 511 (M+1)⁺.

Example 167

The keto-acid intermediate from Example 86 (0.3 g, 0.543 mmol) in DMF(3.5 mL) was added HOBt-NH₂ (0.413 g, 2.717 mmol), and EDCI (0.521 g,2.727 mmol). The resulted mixture was stirred at room temperature for 5h and quenched with water at 5° C. and the precipitate was furtherstirred at room temperature for 40 minutes then filtered, washed withwater and dried to obtain the amide intermediate (0.28 g, 93% yield, 85%purity); MS m/e 552 (M+1), 574(M+Na).

This intermediate (0.13 g, 0.235 mmol) in tetrahydrofuran (5 mL) wasadded lithium borohydride (0.092 g, 4.2 mmol) at 5° C. then stirred atroom temperature for 2 h and quenched with water at 0° C. The aqueouslayer was extracted with a mixture of tetrahydrofuran and ethyl acetate(1:1 ratio) and the combined organics were washed with brine, dried andconcentrated to obtain the crude product. The crude product wastriturated with a mixture of tetrahydrofuran and ethyl acetate at roomtemperature for 1 h, filtered, washed with ether and dried to providethe hydroxy-amide (0.09 g, 75% yield, 79% purity); MS m/e 534 (M+1), 494(M-18). To the amide in methylene chloride (25 mL) was addedtrifluoroacetic acid (8 drops). The resulted mixture was stirred at roomtemperature for 2.5 h then diluted with ethyl acetate and concentratedunder vacuum to furnish the crude product. The crude product waspurified by silica gel column chromatography (0.0074 g, 14% yield); MSm/e 494 (M+1).

Example 168

The keto-methyl ester intermediate prepared using the method of Example78 (0.026 g, 0.057 mmol) in NMP was added hydrazine hydrate (20 drops).The resulted clear solution was heated to 100° C. for 4 hours andquenched with water and the solid was filtered, washed with water anddried, (14 mg, 58% yield); MS m/e 435 (M+1), 457 (M+Na).

Example 169

A mixture of intermediate I-27 (1 eq) and methoxylamine hydrochloride (4eq) in a mixture of 1-methyl-2-pyrrolidinone and ethyl alcohol wasrefluxed for 2 h. Ethyl alcohol was removed under vacuum and thereaction mixture was quenched with water and the resulted solid wasfiltered, washed with water and dried to afford product. MS m/e 440(M+1).

Example 170

A dried flask containing I-22 (100 mg, 0.20 mmol), Cs₂CO₃ (91 mg, 0.25mmol), p-anisidine (117 mg, 0.95 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 0.09 mmol), andPd(OAc)₂ (13 mg, 0.06 mmol) was de-gassed three times. Dry xylenes (5mL) were added and the mixture was again de-gassed three times. Afterheating to 125° C. for 20 h, the black solution was cooled and thesolvent removed in vacuo. Methylene chloride (10 mL) was added, themixture filtered through Celite, and the mother liquor waschromatographed on silica gel (5% MeOH/CH₂Cl₂). The intermediate yielded(22 mg) and Raney nickel (50 mg) was hydrogenated in 5 mL 9:1 DMF/MeOHat room temperature under 50 psi of hydrogen pressure for 4 days,filtered through Celite, and concentrated in vacuo. The resulting brownsolid was triturated with MeOH to yield 9 mg (9%) as a tan powder:mp>300° C.; ¹H NMR (DMSO-d₆) δ 1.37 (t, J=6.9 Hz, 3H), 2.81 (t, J=5.8Hz, 2H), 3.27 (t, J=5.8 Hz, 2H), 3.72 (s, 3H), 3.82 (s, 3H), 4.56 (q,J=6.8 Hz, 2H), 4.70 (s, 2H), 6.80 (dd, J=2.6, 8.7 Hz, 1H), 6.86 (d,J=9.1 Hz, 2H), 6.90 (d, J=2.7 Hz, 1H), 7.1 (d, J=9.1 Hz, 2H), 7.21 (dd,J=2.0, 8.7 Hz, 1H), 7.52 (d, J=2.0 Hz 1H), 7.56 (d, J=8.8 Hz, 1H), 7.78(s, 1H), 7.89 (d, J=8.6 Hz, 1H), 8.26 (s, 1H); MS (m/e) 504 (M+).

Example 171

A dried flask containing I-22 (75 mg, 0.15 mmol), Cs₂CO₃ (68 mg, 0.19mmol), 2,5-dimethoxyaniline (100 mg, 0.71 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15 mg, 0.07 mmol), andPd(OAc)₂ (10 mg, 0.04 mmol) was de-gassed three times. Dry xylenes (5mL) were added and the mixture was again de-gassed three times. Afterheating to 125° C. for 20 h, the black solution was cooled and thesolvent removed in vacuo. Methylene chloride (10 mL) was added, themixture filtered through Celite, and the mother liquor waschromatographed on silica gel (5% MeOH/CH₂Cl₂). The intermediate yielded(22 mg) and Raney nickel (50 mg) was hydrogenated in 5 mL 9:1 DMF/MeOHat room temperature under 50 psi of hydrogen pressure for 4 days,filtered through Celite, and concentrated in vacuo. The resulting brownsolid was triturated with MeOH to yield 6 mg (8%) as a tan powder:mp>300° C.; ¹H NMR (DMSO-d₆) δ 1.39 (t, J=7.1 Hz, 3H), 2.81 (t, J=6.7Hz, 2H), 3.27(t, J=6.7Hz, 2H), 3.63 (s, 3H), 3.82(s, 6H), 4.57 (q, J=6.5Hz, 2H), 4.71 (s, 2H), 6.30 (dd, J=2.9, 8.7 Hz, 1H), 6.72 (d, J=2.8 Hz,1H), 6.81 (dd, J=2.7, 8.7 Hz, 1H), 6.89 (d,J=8.8 Hz, 1H), 6.90 (d, J=3.3Hz, 1 H), 7.28 (s, 1H), 7.40 (dd, J=2.1, 8.7 Hz, 1H), 7.61 (d, J=8.8Hz,1H), 7.73 (d, J=1.8 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 8.31 (s, 1H); MS(m/e) 534 (M+).

Example 172

This compound was prepared by the general method for Example 80 exceptusing nitromethane and methylene chloride as a solvent in step 1 andstarting from the dihydroindazole intermediate I-20 andmethyl-5-chloro-5-oxovalerate. MS (ESI): m/e 413 (M+1)⁺.

Example 173

This compound was prepared by the general method for Example 75 startingfrom intermediate I-20. MS (ESI): m/e 399 (M+1)⁺.

Example 174

This compound was prepared by the general method for Example 100starting from intermediate I-20. MS (ESI): m/e 467 (M+1)⁺.

Example 175

This compound was prepared by the general method for Example 91 andExample 102 starting from intermediate I-20. MS (ESI): m/e 441 (M+1)⁺.

Example 176

This compound was prepared by the general method for Example 103 andExample 86 starting from intermediate I-20. MS (ESI): m/e 441 (M+1)⁺.

Example 177

This compound was prepared from Example 175 and ethyl iodide by thegeneral method for Example 83. MS (ESI): m/e 469 (M+1)⁺.

Example 178

This compound was from Example 175 and bromobutyronitrile by the generalmethod for Example 83. MS (ESI): m/e 508 (M+1)⁺.

Examples 179–242 were prepared from Example 172 and the appropriatebromide or iodide by the general method described from Example 83.

Example 179

MS (ESI): m/e 455 (M+1)⁺

Example 180

MS (ESI): m/e 441 (M+1)⁺.

Example 181

MS (ESI): m/e 427 (M+1)⁺.

Example 182

MS (ESI): m/e 471 (M+1)⁺.

Example 183

MS (ESI): m/e 453 (M+1)⁺.

Example 184

MS (ESI): m/e 485 (M+1)⁺.

Example 185

MS (ESI): m/e 469 (M+1)⁺.

Example 186

MS (ESI): m/e 457 (M+1)⁺.

Example 187

MS (ESI): m/e 481 (M+1)⁺.

Example 188

MS (ESI): m/e 455 (M+1)⁺.

Example 189

MS (ESI): m/e 469 (M+1)⁺.

Example 190

MS (ESI): m/e 451 (M+1)⁺.

Example 191

MS (ESI): m/e 512 (M+1)⁺.

Example 192

MS (ESI): m/e 467 (M+1)⁺.

Example 193

MS (ESI): m/e 483 (M+1)⁺.

Example 194

MS (ESI): m/e 483 (M+1)⁺.

Example 195

MS (ESI): m/e 498 (M+1)⁺.

Example 320

MS (ESI): m/e 483 (M+1)⁺.

Example 196

MS (ESI): m/e 550 (M+1)⁺.

Example 197

MS (ESI): m/e 497 (M+1)⁺.

Example 198

MS (ESI): m/e 469 (M+1)⁺.

Example 199

MS (ESI): m/e 469 (M+1)⁺.

Example 200

MS (ESI): m/e 473 (M+1)⁺.

Example 201

MS (ESI): m/e 487 (M+1)⁺.

Example 202

MS (ESI): m/e 455 (M+1)⁺.

Example 203

MS (ESI): m/e 455 (M+1)⁺.

Example 204

MS (ESI): m/e 481 (M+1)⁺.

Example 205

MS (ESI): m/e 481 (M+1)⁺.

Example 206

MS (ESI): m/e 481 (M+1)⁺.

Example 207

MS (ESI): m/e 509 (M+1)⁺.

Example 208

MS (ESI): m/e 501 (M+1)⁺.

Example 210

MS (ESI): m/e 497 (M+1)⁺.

Example 211

MS (ESI): m/e 523 (M+1)⁺.

Example 212

MS (ESI): m/e 487 (M+1)⁺.

Example 213

MS (ESI): m/e 497 (M+1)⁺.

Example 214

MS (ESI): m/e 469 (M+1)⁺.

Example 215

MS (ESI): m/e 495 (M+1)⁺.

Example 216

MS (ESI): m/e 466 (M+1)⁺.

Example 217

MS (ESI): m/e 469 (M+1)⁺.

Example 218

MS (ESI): m/e 469 (M+1)⁺.

Example 209

To example 172 (50 mg, 0.121 mmol) was added Ac₂O (2 mL), and thereaction mixture was heated to 140° C. for 2 h. The solution was cooledto room temperature, Et₂O was added, and the yellow solid was collectedand dried (33 mg, 60%): ¹H NMR (DMSO-d₆) δ 1.75 (m, 9H), 2.62 (s, 3H),2.88 (m, 2H), 3.25 (m, 2H), 3.89 (s, 3H), 5.17 (s, 2H), 7.44 (d, 1H),7.54 (d, 1H), 7.87 (s, 1H), 8.72 (s, 1H), 11.72 (s, 1H) ppm; MS (m/e)455 (M⁺).

Example 219

This compound was prepared from Example 176 and bromobutyronitrile bythe general method for Example 83. MS (ESI): m/e 508 (M+1)⁺.

Example 220

This compound was prepared from Example 176 and ethyl iodide by thegeneral method for Example 83. MS (ESI): m/e 469 (M+1)⁺.

Examples 221–227 were prepared from Example 176 using the methoddescribed for Example 83.

Example 221

MS (ESI) m/e 497 (M+1).

Example 222

MS (ESI): m/e 455 (M+1)⁺.

Example 223

MS (ESI): m/e 481 (M+1)⁺.

Example 224

MS (ESI): m/e 483 (M+1)⁺.

Example 225

MS (ESI): m/e 509 (M+1)⁺.

Example 226

MS (ESI): m/e 501 (M+1)⁺.

Example 227

MS (ESI): m/e 515 (M+1)⁺.

Example 228

This compound was prepared from Example 173 and ethyl iodide by thegeneral method for Example 83. MS (ESI): m/e 427 (M+1)⁺.

Example 229

This compound was prepared from Example 174 and propyl iodide by thegeneral method for Example 86. MS (ESI): m/e 509 (M+1)⁺.

Example 230

This compound was prepared from Example 174 and ethyl iodide by thegeneral method for Example 83. MS (ESI): m/e 495 (M+1)⁺.

Example 231

This compound was prepared from Example 174 and bromobutyronitrile bythe general method for Example 83. MS (ESI): m/e 534 (M+1)⁺.

Example 232

This compound was prepared from N-acyl aldehyde intermediate I-21 usingthe general procedure described for Example 12–28. MS (ESI): m/e 485(M+1)⁺.

Example 233

This compound was prepared from Example 232 using the deacylation methoddescribed. MS (ESI): m/e 443 (M+1)⁺.

Example 234

This compound was prepared using the general method described forExample 231. MS (ESI): m/e 513 (M+1)⁺.

Example 235

This compound was prepared from Example 234 using the method describedfor Example 233. MS (ESI): m/e 471 (M+1)⁺.

General Procedure for Examples 236–244.

A mixture of intermediate I-24 or I-25 (1 eq) and hydroxylaminehydrochloride or O-alkyl hydroxylamine hydrochloride in a mixture of1-methyl-2-pyrrolidinone and ethyl alcohol was refluxed for 4 h. Ethylalcohol was removed under vacuum then quenched with water and theresulted solid was filtered, washed with water and dried to obtain theproduct.

Example 236

MS m/e 400 (M+1)

Example 237

MS m/e 442 (M+1)

Example 238

MS m/e 453 (M+1)

Example 239

MS m/e 414 (M+1)

Example 240

MS m/e 442 (M+1)

Example 241

MS m/e 426 (M+1)

Example 242

MS m/e 426 (M+1)

Example 243

MS m/e 442 (M+1)

Example 244

MS m/e 428 (M+1).

Example 245

A mixture of intermediate I-24 (1 eq), methanesulfonyl hydrazide (5 eq)and p-toluenesulfonic acid monohydrate (1 eq) in a mixture of1-methyl-2-pyrrolidinone and benzene was refluxed using a Dean-starktrap for 2.5 h. The reaction mixture was quenched with saturated aqueoussodium bicarbonate solution and extracted thrice with a mixture of ethylacetate and tetrahydrofuran (1:1 ratio). The combined organic layerswere washed with brine, dried and concentrated, and the crude productwas triturated with a mixture of tetrahydrofuran, ether and hexane toyield product. MS m/e 463 (M+1)

General Procedure for Examples 246–250.

A mixture of intermediate methyl ketone intermediate I-26 (1 eq) andO-alkyl hydroxylamine hydrochloride (4 eq) in a mixture of1-methyl-2-pyrrolidinone and ethyl alcohol was refluxed for 2 h.Potassium carbonate (17 eq) was added at room temperature and heated to65° C. for 1 h. Ethyl alcohol was removed under vacuum, the reactionmixture was then quenched with water and extracted thrice with a mixtureof tetrahydrofuran and ethyl acetate (1:1 ratio). The combined organicswas washed with brine, dried and concentrated to provide a crudeproduct, which was triturated with a mixture of tetrahydrofuran, etherand hexane to furnish a pure product.

Example 246

MS m/e 470 (M+1)

Example 247

MS m/e 456 (M+1)

Example 248

MS m/e 484 (M+1)

Example 249

MS m/e 498 (M+1)

Example 250

MS m/e 509 (M+1)

Example 251

This compound was prepared from methyl ketone intermediate I-25 usingthe general procedure for Example 246–250. MS m/e 428 (M+1)

Examples 252–286 were prepared using the appropriate N-alkyl ketoneintermediate I-26 by the general oxime synthesis methods described forExamples 246–250.

Example 252

MS m/e 442 (M+1)

Example 253

MS m/e 484 (M+1)

Example 254

MS m/e 470 (M+1)

Example 255

MS m/e 456 (M+1)

Example 256

To the intermediate I-32 (25 mg, 0.07 mmol) in nitromethane (5 mL) wasadded 2-thiophene carbonyl chloride (75 μl 0.7 mmol, 10 eq) followed byaluminum chloride (94 mg, 0.7 mmol, 10 eq) added in small portions. Thereaction mixture was stirred at room temperature overnight. The reactionwas then concentrated, stirred with water and a few drops of 1 N HCladded. The product was collected by filtration, dissolved in methylenechloride/methanol and purified by preparative TLC eluting with 10%methanol/methylene chloride. The desired band was collected, stirredwith methylene chloride/methanol, filtered, and concentrated. The samplewas dried at 80° C. under vacuum overnight. MS m/e 495 (M+1). Example256 was prepared by from thienyl ketone intermediate and hydroxylamineHCl using the general procedure described for Examples 246–249. MS m/e544 (M+1)

Example 257

MS m/e 456 (M+1)

Example 258

MS m/e 442 (M+1)

Example 259

MS m/e 456 (M+1)

Example 260

MS m/e 470 (M+1)

Example 261

MS m/e 484 (M+1)

Example 262

MS m/e 498 (M+1)

Example 263

MS m/e 428 (M+1)

Example 264

MS m/e 442 (M+1)

Example 265

MS m/e 456 (M+1)

Example 266

MS m/e 470 (M+1)

Example 267

MS m/e 490 (M+1)

Example 268

MS m/e 499 (M+1)

Example 269

MS m/e 470 (M+1)

Example 270

MS m/e 484 (M+1)

Example 271

MS m/e 414 (M+1)

Example 272

MS m/e 428 (M+1)

Example 273

MS m/e 456 (M+1)

Example 274

MS m/e 471 (M+1)

Example 275

MS m/e 499 (M+1)

Example 276

MS m/e 485 (M+1)

Example 277

MS m/e 546 (M+1)

Example 278

MS m/e 562 (M+1)

Example 279

MS m/e 511 (M+1)

Example 280

MS m/e 497 (M+1)

Example 281

MS m/e 539 (M+1)

Example 282

MS m/e 525 (M+1)

Example 283

MS m/e 567 (M+1)

Example 284

MS m/e 553 (M+1)

Example 285

MS m/e 595 (M+1)

Example 286

MS m/e 581 (M+1)

Example 287

A mixture of intermediate I-28-1 (98.2 mg, 0.2 mmol), Pd(OAc)₂ (13.4 mg,0.06 mmol), BINAP (56 mg, 0.09 mmol), Cs₂CO₃ (91 mg, 0.28 mmol) andp-anisidine (118 mg, 0.96 mmol) in 5.0 ml of o-xylene was refluxed underN₂ for 18 hr. The reaction was followed by HPLC. The reaction was cooledto room temperature and diluted with CH₂Cl₂, filtered through celite andwashed with CH₂Cl₂. Concentration and purification by flashchromatography with 5% MeOH in CH₂Cl₂ and preparative TLC provided 35 mg(33%) of the 3-substituted cyano ester. MS: 534 m/e (M+H)⁺. A mixture ofthis 3-substituted cyano ester (25 mg, 0.046 mmol), Raney-Ni (excess)and 5.0 mL of DMF and 0.5 mL of MeOH was hydrogenated under 50 psi H₂ ona Parr apparatus overnight at room temperature. The reaction wasmonitored by HPLC to completion. The RaNi was removed by filtration, thesolvent concentrated and the product purified by silica chromatography(5% MeOH in CH₂Cl₂) to afford 16.0 mg (71%) of product. MS: 492 m/e(M+H)⁺.

Example 288

This compound was prepared by the same general procedure as Example 287with intermediate I-28-1 (98.2 mg, 0.2 mmol), Pd(OAc)₂ (13.4 mg, 0.06mmol), BINAP (56 mg, 0.09 mmol), Cs₂CO₃ (91 mg, 0.28 mmol) andN-methylaniline (104 uL, 0.96 mmol) in 5.0 ml of o-xylene. The3-substituted cyano ester (60 mg, 58%) was obtained. MS: 518 m/e (M+H)⁺.Hydrogenation of the 3-substituted cyano ester (50 mg, 0.097 mmol) asdescribed for Example 287 afforded 33 mg (72%) of product. MS: 476 m/e(M+H)⁺.

Example 289

This compound was prepared by the same general procedure as Example 287with intermediate I-28-1 (98.2 mg, 0.2 mmol), Pd(OAc)₂ (13.4 mg, 0.06mmol), BINAP (56 mg, 0.09 mmol), Cs₂CO₃ (91 mg, 0.28 mmol) and2,5-dimethoxyaniline (147 mg, 0.96 mmol) in 5.0 ml of o-xylene. The3-substituted cyano ester (45 mg, 40%) intermediate was obtained. MS:564 m/e (M+H)⁺. Hydrogenation of this 3-substituted cyano ester (40.0mg, 0.07 mmol) as described for Example 287 afforded 31 mg (85%) of theproduct. MS: 522 m/e (M+H)⁺.

Examples 290–306 were prepared using general procedures described forExamples 287–289 starting with the cyano-ester intermediate I-28 and theappropriate aniline.

Example 290

MS m/e 492 (M+1)

Example 291

MS m/e 522 (M+1)

Example 292

MS m/e 522 (M+1)

Example 293

MS m/e 492 (M+1)

Example 294

MS m/e 492 (M+1)

Example 295

MS m/e 521 (M+1)

Example 296

MS m/e 520 (M+1)

Example 297

MS m/e 560 (M+1)

Example 298

MS m/e 522 (M+1)

Example 299

MS m/e 548 (M+1)

Example 300

MS m/e 522 (M+1)

Example 301

MS m/e 506 (M+1)

Example 302

MS m/e 480 (M+1)

Example 303

MS m/e 492 (M+1)

Example 304

MS m/e 506 (M+1)

Example 305

MS m/e 506 (M+1)

Example 306

MS m/e 546 (M+1)

Example 307

This compound was prepared using the N-propyl cyano-ester intermediateI-28-2 and butyrolactam using the coupling and reductive cyclizationprocedure described for Examples 287–289. MS m/e 454 (M+1)

Example 308

This compound was prepared using the N-iso-butyl cyano-esterintermediate I-28-4 and 2-oxo-3,4,5-trihydro-imidazole using thecoupling and reductive cyclization procedure described for Examples287–289. MS m/e 469 (M+1).

Synthesis of Intermediate I-29-1.

Step 1: To 1 g (2.7 mmol) intermediate I-30 in 130 mL acetone was added3.7 mL 10N NaOH, followed by 1.22 mL (12.2 mmol) 2-iodopropane. Thereaction was heated to reflux for 48 hours then concentrated. Water wasadded and the product extracted with methylene chloride and washed withbrine. The organic layer was dried over sodium sulfate, filtered,concentrated, and dried under vacuum at 80° C. to give 830 mg (75%yield) of the N-isopropyl product; MS m/e 413(M+H).

Step 2: To 1.32 g (3.2 mmol) of intermediate from step 1 in 15 mL AcOHwas added 409 μl (6.41 mmol, 2 eq) 70% HNO₃ drop wise at r.t. Thereaction was heated to 80° C. for 2 hours and let stand at r.t.overnight. The solid was collected by filtration, washed with water andether, and dried under vacuum at 80° C. to give 1.1 g (77% yield) of thenitro intermediate; MS m/e 458 (M+H).

Step 3: To 1.1 g (2.47 mmol) of the nitro intermediate from step 3 in 40ml DMF/13 mL MeOH was added a few spatula tips of RaNi under nitrogenatmosphere. The reaction mixture was stirred at 50 psi on a ParrApparatus for 48 hours. The solution was filtered through celite,concentrated under vacuum, suspended and stirred with ether overnight togive 800 mg of intermediate I-29-1 as an off-white solid (86% yield); MSm/e 386(M+H).

Example 309

To 20 mg (0.52 mmol) intermediate I-29-1 in 1 mL n-butanol was added 7mg (0.6) 2-chloropyrimidine, and the reaction was heated to refluxovernight. The reaction mixture was then concentrated, stirred withwater, filtered, and eluted on a silica gel preparative TLC plate using9% MeOH/CH₂Cl₂. The product was collected, stirred with methylenechloride/acetone, filtered, and concentrated. The sample was dried at80° C. under high vacuum overnight to give 11.4 mg as a yellow solid,47% yield MS m/e 464 (M+H).

Examples 310–318 were prepared using the general procedure for Example309.

Example 310

MS m/e 464 (M+1)

Example 311

MS m/e 478 (M+1)

Example 312

MS m/e 464 (M+1)

Example 313

MS m/e 508 (M+1)

Example 314

MS m/e 463 (M+1)

Example 315

MS m/e 546 (M+1)

Example 316

MS m/e 506 (M+1)

Example 317

MS m/e 506 (M+1)

Example 318

MS m/e 492 (M+1)

Example 319

A mixture of cyano-ester intermediate I-30 (500 mg, 1.4 mmol), 10 N NaOH(3 mL), 3-bromo cyclohexene (1 mL) in acetone (30 mL) was stirred atreflux 12 hours. The acetone was removed at reduced pressure, excesswater was added and the product collected by filtration. MS (ES+) m/e451 (M+1). The above intermediate in DMF/MeOH (50 mL, 9:1) and 2 scoopsof RaNi was hydrogenated on a Parr apparatus for 12 hours. The catalystwas removed by filtration and the solvent removed at reduced pressure.MeOH was added to the residue and the product was precipitated byaddition of water to give 580 mg of intermediate product. MS (ES+) m/e411 (M+1). To a stirred suspension of the previous intermediate product(450 mg, 1.1 mmol) in methylene chloride (100 mL) was added3-(carbomethoxy)propionyl chloride (1.5 mL, 11 mmol) then aluminumchloride (1.5 g, 11 mmol) under nitrogen atmosphere. The reaction wasstirred over night at room temperature. The solid was collected, addedto ice water, triturated and collected. The product was chromatographedon silica gel (CH₂Cl₂/MeOH; 95/5). MS (ES+) m/e 539 (M+1). The THP ringwas formed by the general procedure described for Example 93 usingsodium borohydride for the reduction and TFA in dichloromethane forcyclization.

MS (ES+) m/e 495 (M+1).

Example 321

To a stirred solution of aluminum chloride (0.49 g, 3.69 mmol, 10equiv.) in methylene chloride (3 mL)-nitromethane (2 mL) at roomtemperature under nitrogen, was added cyclopentylcarbonyl chloride (0.45mL, 3.69 mmol, 10 equiv.). The solution was stirred at room temperaturefor 15 min. The dihydroindazole template (0.12 g, 3.69 mmol, 1 equiv.)was added as a solid to the reaction mixture. After 24 h at roomtemperature, the reaction mixture was cooled to 0° C. and quenched with10% HCl. The product precipitated out of solution and was collected byfiltration (0.15 g, 97% yield). ¹H NMR (DMSO-d₆): δ 1.55 (m, 1H), 1.67(m, 2H), 1.83 (m, 3H), 1.97 (m, 2H), 2.88 (dd, 2H), 3.26 (dd, 2H), 3.87(s, 3H), 4.004 (m, 1H), 4.89 (s, 2H).7.62 (d, 1H), 8.09 (s, 1H), 8.51(s, 1H), 8.91 (s, 1H), 11.91 (s, 1H); MS (ESI): m/e 425 (M+H)⁺.

Example 322

To a stirred suspension of product from Example 321 (126 mg, 0.297 mmol,1 equiv.) in THF (8 mL) under nitrogen was added lithium borohydride(1.5 mL, 2.97 mmol, 10 equiv.) dropwise. Vigorous evolution of gas wasobserved and gradually the reaction mixture became homogeneous.Additional lithium borohydride (1.5 mL, 2.97 mmol, 10 equiv.) was addedand the mixture was stirred overnight. When no starting material wasobserved by HPLC, the mixture was cooled to 0° C. and quenched slowlyand carefully with water. The solvent was removed in vacuo leaving a tansolid (110 mg, 87% yield). A sample of the solid (40 mg) was purified bypreparatory plate chromatography on silica gel using 10%methanol/methylene chloride to yield the product as an off-white solid(11.6 mg, 29% yield). ¹H NMR (DMSO-d₆): δ 1.23 (m, 2H), 1.43 (m, 1H),1.55 (m, 3H), 1.73 (m, 1H), 2.21 (m, 1H), 2.86 (dd, 2H), 3.23 (dd, 2H),3.88 (s, 3H), 4.42 (m, 1H), 4.77 (s, 2H), 5.07 (d, 1H), 7.40 (d, 1H),7.48 (d, 1H), 7.82 (s, 8.34 (s, 1H), 8.88 (s, 1H), 11.41 (s, 1H); MS(ESI): m/e 427 (M+H)⁺.

Example 323

To a stirred suspension of product from Example 322 (70 mg, 0.164 mmol,1 equiv.) in methylene chloride (8 mL) was added trifloroacetic acid(63.2 μL, 0.820 mmol, 5 equiv.) followed by triethylsilane (0.13 mL,0.820 mmol, 5 equiv.). The reaction mixture became homogeneous and wasstirred at room temperature overnight. Reaction solvent was removed invacuo leaving a tan solid. The solid was purified by preparatory platechromatography using 10% methanol/methylene chloride to yield a tansolid (12.3 mg, 18% yield). ¹H NMR (DMSO-d₆): δ 1.25 (m, 2H), 1.50 (m,2H), 1.65 (m, 4H), 2.19 (m, 1H), 2.74 (d, 2H), 2.86 (dd, 2H), 3.22 (dd,2H), 3.86 (s, 3H), 4.77 (s, 2H), 7.26 (d, 1H), 7.45 (d, 1H), 7.69 (s,1H), 8.34 (s, 1H), 8.88 (s, 1H), 11.38 (s, 1H); MS (ESI): m/e 411(M+H)⁺.

Example 324

This compound was prepared using the general procedure described forExample 321. MS m/e 439 (M+1).

Example 325

This compound was prepared using the general procedure described forExample 322–323. MS m/e 425 (M+1).

Example 326

This compound was prepared using 1-tributylstannyl cyclopentene and the3-bromo intermediate using the same general procedure as Example 39. MSm/e 395 (M+1).

Example 327

This compound was prepared using the same general procedure as Example39, using 1-tributylstannyl cyclopentene and intermediate I-28-1. Theproduct formed was subjected to RaNi/H₂ hydrogenation and the productpurified by silica gel chromatography. MS m/e 439 (M+1).

Example 328

This compound was prepared using the same method as described forExample 9 using intermediate I-31-1. MS m/e 425 (M+1).

Example 329

This compound was prepared using the same method as described forExample 328 using the N-sec-butyl intermediate. MS m/e 481 (M+1).

Example 330

Step 1: To a solution of intermediate I-32 (95 mg, 0.28 mmol) in drymethylene chloride (15 mL) and nitromethane (10 mL) was added3-chloropropionyl chloride (0.24 mL, 2.51 mmol) and then aluminumchloride (335 mg, 2.52 mmol). The reaction was stirred for 20 minutes,when LC-MS and HPLC indicated that the reaction was complete. Thereaction was concentrated via rotary evaporation, and water (50 mL) and1 N HCl (3 mL) were added to the remaining solid and the mixture wasstirred for 1 hour at room temperature. The solid was filtered andwashed with water (150 mL). The remaining solid was dissolved inmethylene chloride and transferred to a sep. funnel, where it was washedwith saturated NaHCO₃ solution, then brine, before drying with MgSO₄.After filtration, the organic layer was concentrated via rotaryevaporation. The remaining solid was purified by silica gelchromatography (95/5 CH₂Cl₂/MeOH), yielding a light yellow solid; (14mg, 0.029 mmol). ¹H NMR (DMSO-d₆) 8.8998 (s, 1H), 8.5374 (s, 1H), 8.4863(s, 1H), 8.1163 (d, 1H, J=6.57 Hz), 7.8673 (d, 1H, J=8.84 Hz), 4.9332(s, 2H), 4.5450 (d, 2H, J=7.07), 4.0058 (t, 2H, J=6.315), 3.8758 (s,3H), 3.7388 (t, 2H, J=5.81), 3.4572 (t, 2H, J=6.32), 2.8429 (t, 2H,J=7.075), 2.1434 (m, 1H), 0.8167 (d, 6H, J=6.82); MS m/e 475 (M+H⁺).

To a solution of the intermediate from step 1 (9 mg, 0.019 mmol) inpyridine (1 mL) was added hydroxylamine hydrochloride (10 mg, 0.144mmol). Additional pyridine (5 mL) was added, and the reaction wasstirred for 20 hours at room temperature before heating the reaction to116° C. After two hours at 116° C., HPLC indicated that the reaction wascomplete. The reaction was concentrated via rotary evaporation, thenpurified by silica gel chromatography (97/3 CH₂Cl₂/MeOH), yielding asolid (9.4 mg, 0.021 mmol, 100% yield). ¹H NMR (CHCl₃) 8.8935 (s, 1H),8.1584 (s, 1H), 7.7629 (dd, 1H, J=1.51, 8.58), 7.4800 (d, 1H, J=8.59),6.1555 (s, 1H), 4.8954 (s, 2H), 4.5418 (t, 2H, J=9.98), 4.4112 (d, 2H,J=7.57), 3.9774 (m, 4H), 2.9837 (t, 2H, J=7.325), 2.2552 (m, 1H), 0.8938(d, 6H, J=6.82); MS m/e 454 (M+H⁺).

Example 332

To a stirring solution of 3-amino intermediate I-29-2 (25 mg, 0.065mmol) in CH₂Cl₂ (5 mL) was added phenyl isothiocyanate (12 μL, 0.098mmol) and pyridine (8 μL, 0.095 mmol). The reaction was heated to 50° C.for 24 h. After cooled to room temperature, the resulted precipitate wascollected by filtration and dried to give 19 mg (56%) of the desiredproduct. ¹H NMR (DMSO-d₆) δ 9.83 (s, 1H), 9.72 (s, 1H), 8.86 (s, 1H),8.39 (s, 1H), 7.99 (s, 1H), 7.66 (m, 1H), 7.50 (m, 3H), 7.34 (m, 2H),7.12 (m, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 3.86 (s, 3H), 3.47 (m, 2H),2.84 (m, 2H), 1.84 (m, 2H), 0.93 (m, 3H); MS (m/e) 521 (M+1).

Example 333

This compound was prepared using the same general procedure as Example332 using 4-methoxyphenyl isothiocyanate. MS (m/e) 551 (M+1).

Example 369

To a stirred solution of 3-amino intermediate I-29-2 (25 mg, 0.065 mmol)in CH₂Cl₂ (5 mL) was added methyl chlorothiolformate (11 μL, 0.130mmol), pyridine (30 μL, 0.371 mmol). After stirring for 24 h at roomtemperature, the resulting precipitate was filtered, dried to give 26 mg(87%) of the desired product. ¹H NMR (DMSO-d₆) δ 10.35 (s, 1H), 8.85 (s,1H), 8.38 (s, 1H), 8.13 (s, 1H), 7.64–7.54 (m, 2H), 4.71 (s, 2H), 4.52(m, 2H), 3.86 (s, 3H), 3.45 (m, 2H), 3.44 (s, 3H), 2.83 (m, 2H), 1.81(m, 2H), 0.89 (m, 3H); MS (m/e) 460 (M+1).

Example 370

This compound was prepared using the general method for Example 369using 3-amino intermediate I-29-2 and ethyl chlorothiolformate. MS (m/e)474 (M+1).

Compounds 331, 334–357, 359–368, 371–380, 384–386 were prepared usingone of methods A–D as outlined below.

Method A. Example 356. To intermediate I-29-1 (20 mg, 0.052 mmol) in 2mL methylene chloride/6.3 μl pyridine was added 10 μl (0.078 mmol, 1.5eq) of 4-methoxyphenyl isocyanate. The reaction was stirred at r.t.overnight. The solid was filtered off and washed with ether and thesample was dried at 80° C. under high vacuum overnight. To give 17 mgs(59% yield) as an off-white solid, MS m/e 535 (M+H).

The following Examples were prepared using method A.

Example 331

MS m/e 535 (M+H).

Example 334

MS m/e 549 (M+H).

Example 335

MS m/e 505 (M+H).

Example 336

MS m/e 535 (M+H).

Example 337

MS m/e 519 (M+H).

Example 338

MS m/e 549 (M+H).

Example 339

MS m/e 519 (M+H).

Example 340

MS m/e 549 (M+H).

Example 341

MS m/e 549 (M+H).

Example 342

MS m/e 537 (M+H).

Example 343

MS m/e 537 (M+H).

Example 344

MS m/e 537 (M+H).

Example 345

MS m/e 535 (M+H).

Example 346

MS m/e 549 (M+H).

Example 347

MS m/e 549 (M+H).

Example 348

MS m/e 523 (M+H).

Example 349

MS m/e 523 (M+H).

Example 350

MS m/e 523 (M+H).

Example 351

MS m/e 537 (M+H).

Example 352

MS m/e 537 (M+H).

Example 353

MS m/e 537 (M+H).

Example 354

MS m/e 537 (M+H).

Example 355

MS m/e 521 (M+H).

Example 356

MS m/e 535 (M+H).

Example 357

MS m/e 505 (M+H).

Example 359

MS m/e 539 (M+H).

Example 360

MS m/e 539 (M+H).

Example 361

MS m/e 583 (M+H).

Example 362

MS m/e 523 (M+H).

Example 363

MS m/e 551 (M+H).

Example 364

MS m/e 519 (M+H).

Example 365

MS m/e 548 (M+H).

Example 366

MS m/e 523 (M+H).

Example 367

MS m/e 539 (M+H).

Example 368

MS m/e 537 (M+H).

Example 371

MS m/e 548 (M+H).

Example 372

MS m/e 539 (M+H).

Example 373

MS m/e 584 (M+H).

Example 374

MS m/e 519 (M+H).

Example 375

MS m/e 511 (M+H).

Example 376

MS m/e 524 (M+H).

Example 377

MS m/e 591 (M+H).

Example 378

MS m/e 591 (M+H).

Example 379

MS m/e 591 (M+H).

Example 380

MS m/e 551 (M+H).

Example 384

MS m/e 551 (M+H).

Example 385

MS m/e 553 (M+H).

Example 386

MS m/e 598 (M+H).

Method B: Example 358. To a stirred solution of 3-amino intermediateI-29-2 (25 mg, 0.0649 mmol) in CH₂Cl₂ (5 mL) was addedN-methyl-N-phenylcarbamoyl chloride (66 mg, 0.389 mmol) and pyridine (80μL, 0.989 mmol). The reaction was heated to 48° C. for 58 h. Aftercooling to room temperature, the reaction was concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography(CH₂Cl₂:MeOH 10:1) to give 24 mg (71%) of the desired product. ¹H NMR(DMSO-d₆) δ 8.45 (s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H),7.57–7.24 (m, 7H), 4.68 (s, 2H), 4.50 (m, 2H), 3.86 (s, 3H), 3.45 (m,2H), 3.32 (s, 3H), 2.83 (m, 2H), 1.80 (m, 2H), 0.89 (m, 3H); MS (m/e)519 (M+1).

Examples 397–401 and 403 were prepared using the method for Example 396.

Example 396

To a stirred solution of intermediate I-29-4 (25 mg, 0.063 mmol) inCH₂Cl₂ (5 mL) was added phenyl chloroformate (0.125 mmol) and pyridine(20 μL, 0.247 mmol). After stirring 3 h at room temperature, theresulting precipitate was filtered and dried to give 28 mg (91%) of thedesired product. MS m/e 520 (M+H).

Example 397

MS m/e 550 (M+H).

Example 398

MS m/e 538 (M+H).

Example 399

MS m/e 506 (M+H).

Example 400

MS m/e 536 (M+H).

Example 401

MS m/e 524 (M+H).

Example 403

MS m/e 506 (M+H).

Method C: Trichloroacetamide intermediate: To 300 mg (0.78 mmol) amineintermediate I-29-1 in 30 mL CH₂Cl₂/95 μl pyridine, was added 174 μl(1.56 mmol, 2 eq) trichloroacetyl chloride at r.t. The reaction wasstirred overnight, concentrated, stirred with water, filtered, and thesolid was washed with ether. The sample was collected and dried at 80°C. under high vacuum to give 392 mg of product (95% yield) ¹H NMR(DMSO-d₆) δ 10.86 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H),7.86 (d, 1H), 7.78 (d, 1H), 5.27 (m, 1H), 4.75 (m, 2H), 3.87 (s, 3H),3.43 (m, 2H), 2.81 (m, 2H), 1.63 (d, 6H). MS m/e 530(M+1).

Example 381

To 20 mg (0.038 mmol) trichloroacetamide intermediate in 1 mL DMF wasadded 8 mg (0.06 mmol, 1.5 eq) potassium carbonate, followed by, 7.2 μl(0.06 mmol, 1.5 eq) 2-(aminoethyl)pyrrolidine. The reaction was heatedto 80° C. overnight, concentrated in vacuo, stirred with water, filteredand collected. The product was purified by preparative silica gel TLCplate eluting with 10% MeOH/CH₂Cl₂. The pure product was collected,stirred with solvent, filtered, concentrated, and dried at 80° C. underhigh vacuum. ¹H NMR (DMSO-d₆) δ 8.77 (s, 1H), 8.72 (s, 1H), 8.35 (s,1H), 8.03 (s, 1H), 7.68 (d, 1H), 7.34 (d, 1H), 6.16 (m, 1H), 5.20 (m,1H), 4.69 (s, 2H), 3.86 (s, 3H), 3.30 (m, 11H), 2.78 (m, 2H), 1.71 (m,3H), 1.58 (d, 6H). MS m/e 526 (M+1).

The following Examples were prepared using method C as described forExample 381.

Example 382

MS m/e 540 (M+1).

Example 383

MS m/e 500 (M+1).

Example 387

MS m/e 569 (M+1).

Example 388

MS m/e 534 (M+1).

Example 389

MS m/e 534 (M+1).

Example 390

MS m/e 533 (M+1).

Example 391

MS m/e 523 (M+1).

Example 392

MS m/e 547 (M+1).

Example 393

MS m/e 548 (M+1).

Method D: N-p-Nitrophenylcarbonate Intermediate: To 484 mg (1.26 mmol)amine intermediate I-29-1 in 50 mL CH₂Cl₂/152 μl pyridine was added 254mg (1.26 mmol, 1.5 eq) 4-nitrophenyl chloroformate. The reaction wasstirred at r.t. overnight then concentrated in vacuo and washed withsodium bicarbonate. The product was collected washed with water anddried at 80° C. under high vacuum to give 616 mg of product (89% yield).

¹H NMR (DMSO-d₆) δ 10.48 (s, 1H), 8.78 (s, 1H), 8.38 (m, 1H), 8.12 (s,1H), 7.82 (d, 1H), 7.75 (m, 2H), 7.58 (m, 3H), 5.24 (m, 1H), 4.69 (s,2H), 3.87 (s, 3H), 3.39 (m, 2H), 2.81 (m, 2H), 1.60 (d, 6H). MS m/e 551(M+1).

Example 394

To 30 mg (0.055 mmol) of the N-Nitrophenylcarbonate Intermediate in 2 mLTHF was added 12 μl (0.082 mmol, 1.5 eq)N,N,N-trimethyl-1,3-propanediamine, and the reaction was heated to 40°C. for 2 hours and concentrated. The crude product was purified bypreparative TLC plate eluting with 10–20% MeOH/CH₂Cl₂. The pure productwas collected, stirred with solvent, filtered, and concentrated. Thesample was dried at 80° C. under high vacuum. ¹H NMR (DMSO-d₆) δ 9.07(s, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H), 7.45(d, 1H), 5.20 (m, 1H), 4.69 (s, 2H), 3.86 (s, 3H), 2.91 (m, 3H), 2.78(m, 2H), 2.3 (m, 11H), 1.72 (m, 3H), 1.59 (d, 6H). MS m/e 528 (M+1).

Example 395

This compound was prepared using p-nitrophenylcarbonate intermediate andN,N,N, trimethyl ethylenediamine by the method described for Example394. MS m/e 514 (M+1).

Example 396

To 25 mg (0.045 mmol) of the N-p-nitrophenyl intermediate was added 500μl N-piperidinylethanol. The reaction was stirred at r.t for ˜5 hours,diluted with methylene chloride, washed with water/brine and dried oversodium sulfate. The crude product was purified by preparative TLC plateeluting with 8–10% MeOH/CH₂Cl₂. The pure product was collected, stirredwith solvent, filtered, and concentrated. The sample was dried at 80° C.under high vacuum. ¹H NMR (DMSO-d₆) δ 9.80 (s, 1H), 8.77 (s, 1H), 8.36(s, 1H), 8.10 (s, 1H), 7.72 (d, 1H), 7.50 (d, 1H), 5.20 (m, 1H), 4.78(s, 2H), 4.19 (m, 2H), 3.86 (s, 3H), 2.78 (m, 2H), 2.41 (m, 4H), 1.59(d, 6H), 1.40 (m, 10H). MS m/e 541 (M+1).

Example 402

To a stirring solution of 3-amino intermediate I-29-2 (25 mg, 0.0649mmol) in CH₂Cl₂ (5 mL) was added dimethylsulfamoyl chloride (35 μL,0.325 mmol), pyridine (100 μL, 1.24 mmol). The reaction was heated to48° C. for 58 h. After cooled to room temperature, the reaction wasconcentrated in vacuo. The residue was purified by preparative thinlayer chromatography (CH₂Cl₂:MeOH 10:1) to give 22 mg (69%) of thedesired product. ¹H NMR (DMSO-d₆) δ 9.74 (s, 1H), 8.86 (s, 1H), 8.38 (s,1H), 7.72 (s, 1H), 7.64 (d, 1H), 7.37 (d, 1H), 4.71 (s, 2H), 4.52 (m,2H), 3.86 (s, 3H), 3.45 (m, 2H), 2.84 (m, 2H), 2.70 (s, 6H), 1.82 (m,2H), 0.91 (m, 3H); MS (m/e) 493 (M+1).

General Procedures for Examples 404–430.

O-Nitrophenylcarbonate intermediate: Step 1: A mixture of the phenolintermediate I-33-1 (192 mg, 0.525 mmol) and p-nitrophenyl carbonate(314 mg, 1.03 mmol) in DMF (4 mL) was heated to 100° C. for 20 h.Solvent was removed by rotary evaporation and the residue was extractedinto CH₂Cl₂ and washed with aqueous NaHCO₃. The organic layer was driedover MgSO₄, filtered, and evaporated. The resulting residue was purifiedby column chromatography (silica gel, 3% MeOH in CH₂Cl₂) to affordproduct (156 mg, 56%). ¹H NMR (CDCl₃) δ 8.86 (s, 1H), 8.34 (d, 2H,J=9.1), 7.69 (d, 1H, J=2.1), 7.53 (d, 2H, J=9.1), 7.49, (d, 1H, J=8.8),7.41, (d, 1H, J=8.8), 6.01 (s, 1H), 4.84 (s, 2H), 4.62 (q, 2H, J=7.1),3.96 (s, 3H), 3.55 (t, 2H, 8.0), 3.01 (t, 2H, J=8.0), 1.55 (t, 3H,J=7.1). MS m/e 538 (M+H).

A suspension of the carbonate intermediate in THF (2 mL) was treatedwith the amine (2.5 eq) and warmed to 40° C. for 2 h. Solvent wasremoved by rotary evaporation, and the residue was extracted into CH₂Cl₂and washed with dilute aqueous NaOH. The organic layer was dried overMgSO₄, filtered, and evaporated. The resulting residue was purified bytriturating with water (2×1 mL) and ether (2×1 mL).

Example 404

MS m/e 541 (M+H).

Example 405

MS m/e 529 (M+H).

Example 406

MS m/e 521 (M+H).

Example 407

MS m/e 569 (M+H).

Example 408

MS m/e 548 (M+H).

Example 409

MS m/e 549 (M+H).

Example 410

MS m/e 538 (M+H).

Example 411

MS m/e 535 (M+H).

Example 412

MS m/e 537 (M+H).

Example 413

MS m/e 541 (M+H).

Example 414

MS m/e 563 (M+H).

Example 415

MS m/e 539 (M+H).

Example 416

MS m/e 560 (M+H).

Example 417

MS m/e 543 (M+H).

Example 418

MS m/e 552 (M+H).

Example 419

MS m/e 537 (M+H).

Example 420

MS m/e 551 (M+H).

Example 421

MS m/e 563 (M+H).

Example 422

MS m/e 524 (M+H).

Example 423

MS m/e 590 (M+H).

Example 424

MS m/e 535 (M+H).

Example 425

MS m/e 549 (M+H).

Example 426

MS m/e 591 (M+H).

Example 427

MS m/e 535 (M+H).

Example 428

MS m/e 577 (M+H).

Example 429

MS m/e 619 (M+H).

Example 430

MS m/e 617 (M+H).

Example 431

This compound was prepared using the same procedure as Example 172,starting with intermediate I-34. MS m/e 413 (M+1).

The following Examples 432–442 were prepared from Example 431 using theappropriate bromide or iodide by the general method described forExamples 179–195.

Example 432

MS m/e 469 (M+H).

Example 433

MS m/e 469 (M+H).

Example 434

MS m/e 481 (M+H).

Example 435

MS m/e 441 (M+H).

Example 436

MS m/e 455 (M+H).

Example 437

MS m/e 455 (M+H).

Example 438

MS m/e 427 (M+H).

Example 439

MS m/e 467 (M+H).

Example 440

MS m/e 485 (M+H).

Example 441

MS m/e 471 (M+H).

Example 442

MS m/e 457 (M+H).

Example 443

was prepared using the same method as Example 289 starting withN-isopropyl intermediate I-35 and 2,5-dimethoxyaniline; MS m/e 522(M+H).

Example 444

This compound was prepared using the intermediate I-37 by the generalprocedure described for Example 309. MS m/e 478 (M+H).

Example 445

This compound was prepared using the intermediate I-38 by the generalprocedure described for Examples 236–244. MS m/e 442 (M+H).

Example 446

This compound was prepared using the intermediate I-38 by the generalprocedure described for Examples 236–244. MS m/e 456 (M+H).

Example 447

This compound was prepared using the intermediate I-37 by the generalprocedure described for Example 287. MS m/e 477 (M+H).

Example 448

This compound was prepared using the intermediate I-37 by the generalprocedure described for Example 447. MS m/e 450 (M+H).

Utility

The compounds of the present invention are useful, inter alia, astherapeutic agents. Particularly, the compounds are useful for kinaseinhibition, such as, for example, trk, VEGFR, PDGFR, PKC, MLK, DLK,Tie-2, FLT-3, and CDK1-6. Various compounds of the present inventionshow enhanced pharmaceutical properties over those disclosed in the artand improved pharmacokinetic properties in mammals. The compounds of thepresent invention show enhanced pharmaceutical properties over thosedisclosed in the art, including increased MLK and DLK dual inhibitionactivity, or increased VEGFR and Tie-2 dual inhibition activity, alongwith improved pharmacokinetic properties in mammals. For example,compounds of the present invention, including those in which at leastone of R³, R⁴, R⁵, and R⁶ is NR¹¹R³² or optionally substituted-(alkylene)_(x)-heterocycloalkyl, wherein the heterocycloalkyl does notinclude unsubstituted N-morpholinyl, N-piperidyl, or N-thiomorpholinyl,wherein said alkylene group is optionally substituted with one to threeR¹⁰ groups, have been shown to increase MLK and DLK inhibition activity.In another example, compounds of the present invention, including thosein which at least one of R³, R⁴, R⁵, and R⁶ is NR¹¹R³³, show increasedVEGFR and Tie-2 inhibition activity.

In one embodiment, the present invention provides a method for treatingor preventing diseases and disorders, such as those disclosed herein,which comprises administering to a subject in need of such treatment orprevention a therapeutically effective amount of a compound of thepresent invention.

In an additional embodiment, the present invention provides a method forinhibiting trk kinase activity comprising providing a compound of thepresent invention in an amount sufficient to result in effectiveinhibition. Particularly, inhibition of trk implies utility in, forexample, diseases of the prostate such as prostate cancer and benignprostate hyperplasia, as well as for the treatment of inflammation, suchas neurological inflammation and chronic arthritis inflammation. In apreferred embodiment, the trk kinase receptor is trk A.

The majority of cancers have an absolute requirement for angiogenesis,the process by which new blood vessels are formed. The most potentangiogenic cytokine is vascular endothelial growth factor (VEGF) andthere has been substantial research into the development of VEGF/VEGFreceptor (VEGFR) antagonists. Receptor tyrosine kinase (RTK) inhibitorscould have broad spectrum antitumor activity in patients with advancedpre-treated breast and colorectal carcinoma and Kaposi's sarcoma.Potentially these agents may play a role in the treatment of both early(adjuvant) and advanced cancer. The importance of angiogenesis for theprogressive growth and viability of solid tumors is well established.Emerging data suggest an involvement of angiogenesis in thepathophysiology of hematologic malignancies as well. Recently, authorshave reported increased angiogenesis in the bone marrow of patients withacute myeloid leukemia (AML) and normalization of bone marrowmicrovessel density when patients achieved a complete remission (CR)after induction chemotherapy. Tumor angiogenesis depends on theexpression of specific mediators that initiate a cascade of eventsleading to the formation of new microvessels. Among these, VEGF(vascular endothelial growth factor), FGF (fibroblast growth factor)play a pivotal role in the induction of neovascularization in solidtumors. These cytokines stimulate migration and proliferation ofendothelial cells and induce angiogenesis in vivo. Recent data suggestan important role for these mediators in hematologic malignancies aswell. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus,the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in anautocrine and paracrine manner. Therefore, neovascularization andangiogenic mediators/receptors may be promising targets foranti-angiogenic and anti-leukemic treatment strategies. Thus, in otherembodiments, the present invention provides a method for treating orpreventing angiogenic disorders where VEGFR kinase activity contributesto pathological conditions, the method comprising providing a compoundof the present invention in an amount sufficient to result in thevascular endothelial growth factor receptor being contacted with aneffective inhibitory amount of the compound. Inhibition of VEGFR impliesutility in, for example, angiogenic disorders such as cancer of solidtumors, endometriosis, macular degeneration, retinopathy, diabeticretinopathy, psoriasis, hemangioblastoma, as well as other oculardiseases and cancers.

FLT3, a member of the receptor tyrosine kinase (RTK) class III, ispreferentially expressed on the surface of a high proportion of acutemyeloid leukemia (AML) and B-lineage acute lymphocytic leukemia (ALL)cells in addition to hematopoietic stem cells, brain, placenta andliver. An interaction of FLT3 and its ligand has been shown to play animportant role in the survival, proliferation and differentiation of notonly normal hematopoetic cells but also leukemia cells. Mutations of theFLT3 gene was first reported as an internal tandem duplication (ITD) ofthe juxtamembrane (JM) domain-coding sequence, subsequently as amissense mutation of D835 within a kinase domain. ITD- andD835-mutations are essentially found in AML and their frequencies areapproximately 20 and 6% of adults with AML, respectively. Thus, mutationof the FLT3 gene is so far the most frequent genetic alteration reportedto be involved in AML. Several large-scale studies in well-documentedpatients published to date have demonstrated that ITD-mutation isstrongly associated with leukocytosis and a poor prognosis. An inhibitorcompound of FLT3 tyrosine kinase have an application in treatment ofleukemia. The present invention provides a method for treating disorderscharacterized by responsiveness to FLT3 inhibition, the methodcomprising providing a compound of the present invention in an amountsufficient to result in the inhibition of FLT3.

Platelet-derived growth factor (PDGF) was one of the first polypeptidegrowth factors identified that signals through a cell surface tyrosinekinase receptor (PDGF-R) to stimulate various cellular functionsincluding growth, proliferation, and differentiation. Since then,several related genes have been identified constituting a family ofligands (primarily PDGF A and B) and their cognate receptors (PDGF-Ralpha and beta). To date, PDGF expression has been shown in a number ofdifferent solid tumors, from glioblastomas to prostate carcinomas. Inthese various tumor types, the biologic role of PDGF signaling can varyfrom autocrine stimulation of cancer cell growth to more subtleparacrine interactions involving adjacent stroma and even angiogenesis.Thus, in additional embodiments, the present invention provides a methodfor treating or preventing disorders where PDGFR activity contributes topathological conditions, the method comprising providing a compound ofthe present invention in an amount sufficient to result in the plateletderived growth factor receptor being contacted with an effectiveinhibitory amount of the compound. Inhibition of PDGFR implies utilityin, for example, various forms of neoplasia, rheumatoid arthritis,chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal woundhealing, diseases with cardiovascular end points, such asatherosclerosis, restenosis, post-angioplasty restenosis, and the like.

In further embodiments, the present invention provides a method fortreating or preventing disorders where MLK activity contributes topathological conditions, such as those listed above, wherein the methodcomprises providing a compound of the present invention in an amountsufficient to result in the MLK receptor being contacted with aneffective inhibitory amount of the compound. Inhibition of MLK impliesutility in, for example, forms of cancer where MLKs play a pathologicalrole as well as in neurological disorders.

In still other embodiments, the present invention provides a method fortreating disorders characterized by the aberrant activity of trophicfactor responsive cells, the method comprising providing a compound ofthe present invention in an amount sufficient to result in the trophicfactor cell receptor being contacted with an effective activity inducingamount of the compound. In certain preferred embodiments, the activityof the trophic factor responsive cells is ChAT activity.

Fibroblast growth factor receptors (FGFR) are members of a family ofpolypeptides synthesized by a variety of cell types during the processesof embryonic development and in adult tissues. FGFR have been detectedin normal and malignant cells and are involved in biological events thatinclude mitogenic and angiogenic activity with a consequent crucial rolein cell differentiation and development. To activate signal transductionpathways, FGFR are coupled to fibroblast growth factors (FGF) andheparan sulfate (HS) proteoglycans to form a biologically fundamentalternary complex. Based on these considerations, inhibitors able to blockthe signaling cascade through a direct interaction with FGFR could haveantiangiogenesis and subsequent antitumor activity. Accordingly, thepresent invention provides a method for treating disorders characterizedby the aberrant activity of FGF responsive cells, the method comprisingproviding a compound of the present invention in an amount sufficient toresult in the FGFR being contacted with an effective activity inducingamount of the compound.

The compounds of the present invention can also have positive effects onthe function and survival of trophic factor responsive cells bypromoting the survival of neurons. With respect to the survival of acholinergic neuron, for example, the compound may preserve the survivalof a cholinergic neuronal population at risk of dying (due to, e.g.,injury, a disease condition, a degenerative condition or naturalprogression) when compared to a cholinergic neuronal population notpresented with such compound, if the treated population has acomparatively greater period of functionality than the non-treatedpopulation.

A variety of neurological disorders are characterized by neuronal cellswhich are dying, injured, functionally compromised, undergoing axonaldegeneration, at risk of dying, etc. These neurodegenerative diseasesand disorders include, but are not limited to, Alzheimer's disease;motor neuron disorders (e.g. amyotrophic lateral sclerosis); Parkinson'sdisease; cerebrovascular disorders (e.g., stroke, ischemia);Huntington's disease; AIDS dementia; epilepsy; multiple sclerosis;peripheral neuropathies including diabetic neuropathy and chemotherapyinduced peripheral neuropathy, AID related peripheral neuropathy;disorders induced by excitatory amino acids; and disorders associatedwith concussive or penetrating injuries of the brain or spinal cord.

In other preferred embodiments, the compounds of the present inventionare useful for treating or preventing multiple myeloma and leukemiasincluding, but not limited to, acute myelogenous leukemia, chronicmyelogenous leukemia, acute lymphocytic leukemia, and chroniclymphocytic leukemia.

In additional embodiments, the present compounds are also useful in thetreatment of disorders associated with decreased ChAT activity or thedeath, injury to spinal cord motoneurons, and also have utility in, forexample, diseases associated with apoptotic cell death of the centraland peripheral nervous system, immune system and in inflammatorydiseases. ChAT catalyzes the synthesis of the neurotransmitteracetylcholine, and it is considered an enzymatic marker for a functionalcholinergic neuron. A functional neuron is also capable of survival.Neuron survival is assayed by quantification of the specific uptake andenzymatic conversion of a dye (e.g., calcein AM) by living neurons. Thecompounds described herein may also find utility in the treatment ofdisease states involving malignant cell proliferation, such as manycancers.

The compounds of the present invention have important functionalpharmacological activities which find utility in a variety of settings,including both research and therapeutic arenas. For ease ofpresentation, and in order not to limit the range of utilities for whichthese compounds can be characterized, the activities of the compounds ofthe present invention can be generally described as follows:

A. Inhibition of enzymatic activity

B. Effect on the function and/or survival of trophic factor responsivecells

C. Inhibition of inflammation-associated responses

D. Inhibition of cell growth associated with hyperproliferative states

E. Inhibition of developmentally programmed motoneuron death

Inhibition of enzymatic activity can be determined using, for example,VEGFR inhibition (e.g., VEGFR2 inhibition), MLK inhibition (e.g., MLK1,MLK2 or MLK3 inhibition), PDGFR kinase inhibition, NGF-stimulated trkphosphorylation, PKC inhibition, or trk tyrosine kinase inhibitionassays. Effect on the function and/or survival of trophic factorresponsive cells, e.g., cells of a neuronal lineage, can be establishedusing any of the following assays: (1) cultured spinal cord cholineacetyltransferase (“ChAT”) assay; (2) cultured dorsal root ganglion(“DRG”) neurite extension assay; (3) cultured basal forebrain neuron(“BFN”) ChAT activity assay. Inhibition of inflammation-associatedresponse can be established using an indoleamine 2,3-dioxygenase (“IDO”)mRNA assay. Inhibition of cell growth associated with hyperproliferativestates can be determined by measuring the growth of cell lines ofinterest, such as an AT2 line in the case of prostate cancer. Inhibitionof developmentally programmed motoneuron death can be assessed in ovousing embryonic chick somatic motoneurons, which cells undergo naturallyoccurring death between embryonic days 6 and 10, and analyzinginhibition of such naturally occurring cell death as mediated by thecompounds disclosed herein.

The inhibition of enzymatic activity by the compounds of the presentinvention can be determined using, for example, the following assays:

VEGFR Inhibition Assay

MLK Inhibition Assay

PKC Activity Inhibition Assay

trkA Tyrosine Kinase Activity Inhibition Assay

Tie-2 Inhibition Assay

CDK1-6 Inhibition Assay

Inhibition of NGF-stimulated trk phosphorylation in a whole cellpreparation

Platelet Derived Growth Factor Receptor (PDGFR) inhibition assay

A description of assays that may be used in connection with the presentinvention are set forth below. They are not intended, nor are they to beconstrued, as limiting the scope of the disclosure.

Inhibition of trkA Tyrosine Kinase Activity

Selected compounds of the present invention were tested for theirability to inhibit the kinase activity of baculovirus-expressed humantrkA cytoplasmic domain using an ELISA-based assay as previouslydescribed (Angeles et al., Anal. Biochem. 236: 49–55, 1996). Briefly,the 96-well microtiter plate was coated with substrate solution(recombinant human phospholipase C-γ1/glutathione S-transferase fusionprotein (Rotin et al., EMBO J., 11: 559–567, 1992). Inhibition studieswere performed in 100 μl assay mixtures containing 50 mM Hepes, pH 7.4,40 μM ATP, 10 mM MnCl₂, 0.1% BSA, 2% DMSO, and various concentrations ofinhibitor. The reaction was initiated by addition of trkA kinase andallowed to proceed for 15 minutes at 37° C. An antibody tophosphotyrosine (UBI) was then added, followed by a secondaryenzyme-conjugated antibody, alkaline phosphatase-labelled goatanti-mouse IgG (Bio-Rad). The activity of the bound enzyme was measuredvia an amplified detection system (Gibco-BRL). Inhibition data wereanalyzed using the sigmoidal dose-response (variable slope) equation inGraphPad Prism. The concentration that resulted in 50% inhibition ofkinase activity is referred to as “IC₅₀”.

Inhibition of Vascular Endothelial Growth Factor Receptor KinaseActivity

Selected compounds of the present invention were examined for theirinhibitory effects on the kinase activity of baculovirus-expressed VEGFreceptor (human flk-1, KDR, VEGFR2) kinase domain using the proceduredescribed for the trkA kinase ELISA assay described above. The kinasereaction mixture, consisting of 50 mM Hepes, pH 7.4, 40 μM ATP, 10 mMMnCl₂, 0.1% BSA, 2% DMSO, and various concentrations of inhibitor, wastransferred to PLC-γ/GST-coated plates. VEGFR kinase was added and thereaction was allowed to proceed for 15 min. at 37° C. Detection ofphosphorylated product was accomplished by addition ofanti-phosphotyrosine antibody (UBI). A secondary enzyme-conjugatedantibody was delivered to capture the antibody-phosphorylated PLC-γ/GSTcomplex. The activity of the bound enzyme was measured via an amplifieddetection system (Gibco-BRL). Inhibition data were analyzed using thesigmoidal dose-response (variable slope) equation in GraphPad Prism.

Inhibition of Mixed Lineage Kinase-1 Activity

The kinase activity of MLK1 was assessed using the Millipore MultiscreenTCA “in-plate” format as described for protein kinase C (Pitt & Lee, J.Biomol. Screening, 1: 47–51, 1996). Briefly, each 50-μl assay mixturecontained 20 mM Hepes, pH 7.0, 1 mM EGTA, 10 mM MgCl₂, 1 mM DTT, 25 mMβ-glycerophosphate, 60 μM ATP, 0.25 μCi [γ-³²P]ATP, 0.1% BSA, 500 μg/mlmyelin basic protein (UBI #13–104), 2% DMSO, 1 μM of test compound, and1 μg/ml of baculoviral GST-MLK1_(KD). Samples were incubated for 15 minat 37° C. The reaction was stopped by adding ice cold 50% TCA and theproteins were allowed to precipitate for 30 min at 4° C. The plates werethen washed with ice cold 25% TCA. Supermix scintillation cocktail wasadded, and the plates were allowed to equilibrate for 1–2 hours prior tocounting using the Wallace MicroBeta 1450 PLUS scintillation counter.

Dual Leucine Zipper Bearing Kinase Assay

Compounds were tested for their ability to inhibit the kinase activityof recombinant baculoviral human DLK, containing the kinase domain andleucine zipper. Activity was measured in 384-well FluoroNunc plates(Cat#460372) using a time-resolved fluorescence readout (PerkinElmerApplication Note 1234–968). Plates were coated with 30 μl of the proteinsubstrate MKK7 (Merritt et al. 1999) at a concentration of 20 μg/ml inTris buffered saline (TBS). Each 30 μl assay contained 20 mM MOPS (pH7.2), 15 mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM DTT, 5 mM EGTA, 25 mMβ-glycerophosphate, 0.1% BSA, 100 μM ATP, and 2.5% DMSO. Reactions werestarted by the addition of 10 ng/ml GST-hDLK_(KD/LZ). For IC₅₀determinations, a 10-point dose response curve was generated for eachcompound. Plates were incubated at 37° C. for 30 minutes, and thereactions stopped by the addition of 100 mM EDTA. Product was detectedusing Europium-labeled anti-phosphothreonine (Wallac#AD0093; diluted1:10000 in 3% BSA/T-TBS). Following overnight capture at 4° C., 50 μlenhancement solution (Wallac #1244-105) was added and the plate gentlyagitated for 5 min. The fluorescence of the resulting solution was thenmeasured using the time-resolved fluorescence (TRF) mode in theMultilabel Reader (Victor2 Model # 1420-018 or Envision Model # 2100).Inhibition data was analyzed using GraphPad PRISM. See also Merritt, S.E., Mata, M., Nihalani, D., Zhu, C., Hu, X., and Holzman, L. B. (1999)The Mixed Lineage Kinase DLK utilizes MKK7 and not MKK4 as Substrate. J.Biol. Chem. 274, 10195–10202.

Tie-2 Tyrosine Kinase Assay

Compounds were tested for their ability to inhibit the kinase activityof recombinant baculoviral human His₆-Tie2 cytoplasmic domain using amodification of the ELISA described for trkA (Angeles et al., 1996). A384-well plate format was used for single-point screening while IC₅₀swere performed on 96-well plates. For single-point screening, eachbarcoded 384-well Costar High Binding plate (Cat # 3703) was coated with50 μl well of 10 μg/ml substrate solution (recombinant human GST-PLC-γ;Rotin et al., 1992) in Tris-buffered saline (TBS). The Tie2 activity wasmeasured in 50-μl assay mixtures containing 50 mM HEPES (pH 7.2), 40 μMATP, 10 mM MnCl₂, 2.5% DMSO, 0.05% BSA, and 200 ng/ml His₆-Tie2_(CD).For IC₅₀ determinations, the assays were run as described above but in96-well Costar High Binding plates (Cat # 3703) and with the volumesdoubled. A 10-point dose response curve was generated for each compound.The kinase reaction was allowed to proceed at 37° C. for 20 minutes. Thedetection antibody, N1-Eu anti-phosphotyrosine (PT66) antibody (Wallac#AD0041), was added at 1:2000 diluted in block buffer [3% BSA in TBSwith 0.05% Tween-20 (TBST)]. After one-hour incubation at 37° C., 50 μlof enhancement solution (Wallac #1244-105) was added and the plate wasgently agitated. The fluorescence of the resulting solution was thenmeasured using the time-resolved fluorescence (TRF) mode in theMultilabel Reader (Victor2 Model # 1420-018 or Envision Model # 2100).Inhibition data were analyzed using ActivityBase and IC₅₀ curves weregenerated using XLFit. The cited references are as follows:

-   -   1. Angeles, T. S., Steffler, C., Bartlett, B. A., Hudkins, R.        L., Stephens, R. M., Kaplan, D. R., and Dionne, C. A. (1996)        Enzyme-linked immunosorbent assay for trkA tyrosine kinase        activity. Anal. Biochem. 236, 49–55.    -   2. Rotin, D., Margolis, B., Mohammadi, M., Daly, R. J., Daum,        G., Li, N., Fischer, E. H., Burgess, W. H., Ullrich, A.,        Schlessinger, J. (1992) SH2 domains prevent tyrosine        dephosphorylation of the EGF receptor: identification of Tyr992        as the high-affinity binding site for SH2 domains of        phospholipase C-γ. EMBO J. 11, 559–567.        Dosage and Formulation

For therapeutic purposes, the compounds of the present invention can beadministered by any means that results in the contact of the activeagent with the agent's site of action in the body of the subject. Thecompounds may be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in combination with other therapeutic agents, suchas, for example, analgesics. The compounds of the present invention arepreferably administered in therapeutically effective amounts for thetreatment of the diseases and disorders described herein to a subject inneed thereof.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, theformulation of the active agent with appropriate excipients, and theroute of administration. Typically, the compounds are administered atlower dosage levels, with a gradual increase until the desired effect isachieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A preferred daily dose for adult humans includesabout 25, 50, 100 and 200 mg, and an equivalent dose in a human child.The compounds may be administered in one or more unit dose forms. Theunit dose ranges from about 1 to about 500 mg administered one to fourtimes a day, preferably from about 10 mg to about 300 mg, two times aday. In an alternate method of describing an effective dose, an oralunit dose is one that is necessary to achieve a blood serum level ofabout 0.05 to 20 μg/ml in a subject, and preferably about 1 to 20 μg/ml.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The excipients are selected onthe basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000. The compositionsmay be formulated to control and/or delay the release of the activeagent(s), as in fast-dissolve, modified-release, or sustained-releaseformulations. Such controlled-release, or extended-release compositionsmay utilize, for example biocompatible, biodegradable lactide polymers,lactide/glycolide copolymers, polyoxyethylene-polyoxypropylenecopolymers, or other solid or semisolid polymeric matrices known in theart.

The compositions can be prepared for administration by oral means;parenteral means, including intravenous, intramuscular, and subcutaneousroutes; topical or transdermal means; transmucosal means, includingrectal, vaginal, sublingual and buccal routes; ophthalmic means; orinhalation means. Preferably the compositions are prepared for oraladministration, particularly in the form of tablets, capsules or syrups;for parenteral administration, particularly in the form of liquidsolutions, suspensions or emulsions; for intranasal administration,particularly in the form of powders, nasal drops, or aerosols; or fortopical administration, such as creams, ointments, solutions,suspensions aerosols, powders and the like.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidones; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; or flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the afore listedexcipients, and may additionally contain a semi-solid or liquid carrier,such as a polyethylene glycol. The solid oral dosage forms may havecoatings of sugar, shellac, or enteric agents. Liquid preparations maybe in the form of aqueous or oily suspensions, solutions, emulsions,syrups, elixirs, etc., or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assurfactants, suspending agents, emulsifying agents, diluents, sweeteningand flavoring agents, dyes and preservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers, and the like. Theparenteral preparations can be enclosed in ampules, disposable syringesor multiple dose vials. Other potentially useful parenteral deliverysystems for the active compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be presented as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably presented as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described herein, and the scope of the invention isintended to encompass all such variations.

1. A compound of Formula II:

wherein: ring B, together with the carbon atoms to which it is attached,is a 5-membered aromatic ring in which either (1) one carbon atom may bereplaced with an oxygen, nitrogen, or sulfur atom; (2) two carbon atomsmay be replaced with a sulfur and a nitrogen atom, an oxygen and anitrogen atom, or two nitrogen atoms; or (3) three carbon atoms may bereplaced with three nitrogen atoms, one oxygen and two nitrogen atoms,or one sulfur and two nitrogen atoms; A¹ and A² are independentlyselected from H, H; H, OR; H, SR; H, N(R)₂; B¹ and B² together form amoiety ═O; R is independently selected from H, and optionallysubstituted alkyl, wherein said optional substituents are one to threeR¹⁰ groups; R¹ is independently selected from H,C(═O)R^(1a),—C(═O)NHR^(1b), and optionally substituted alkyl, whereinsaid optional substituents are one to three R¹⁰ groups; R^(1a) isindependently selected from optionally substituted alkyl, optionallysubstituted aryl and optionally substituted heteroaryl, wherein saidoptional substituents are one to three R¹⁰ groups; R^(1b) isindependently selected from H and optionally substituted alkyl, whereinsaid optional substituents are one to three R¹⁰ groups; R² is selectedfrom H, C(═O)R^(2a), C(═O)NR^(2c)R^(2d), CO₂R^(2b),-optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, and optionally substituted cycloalkyl, wherein saidoptional substituents are one to three R¹⁰ groups; R^(2a) isindependently selected from optionally substituted alkyl, optionallysubstituted aryl, OR^(2b), and NR^(2c)R^(2d), wherein said optionalsubstituents are one to three R¹⁰ groups; R^(2b) is selected from H andoptionally substituted alkyl, wherein said optional substituents are oneto three R¹⁰ groups; R^(2c) and R^(2d) are each independently selectedfrom H and optionally substituted alkyl, or together with the nitrogento which they are attached form an optionally substitutedheterocycloalkyl, wherein said optional substituents are one to threeR¹⁰ groups; at least one of R³, R⁴, R⁵, and R⁶ is selected from(alkylene)_(x)OR¹³, C(═O)R¹³, (CH₂)_(p)OR²², O-(alkylene)-R²⁷,OCH(CO₂R¹⁸)₂, OCH[(CH₂)_(p)OR²⁰]₂, C(═O)-(alkylene)-R²⁵, —NR¹¹R³²,NR¹¹R³³, (alkylene)-NR¹⁸R¹⁹, C(R¹²)═N—R¹⁸, CH═N—OR¹³, C(R¹²)═N—OR²⁰,C(R¹¹)═N—NR¹¹C(═O)NR^(14A)R^(14B), C(R¹¹)═N—NR¹¹SO₂R¹⁸,OC(═O)NR¹¹(alkylene)-R²⁶, OC(═O)[N(CH₂CH₂)₂N]—R²¹, NR¹¹C(═O)OR²³,NR¹¹C(═O)S—R¹⁸, NR¹¹C(═O)NR¹¹R²³, NR¹¹C(═S)NR¹¹R²³, NR¹¹S(═O)₂N(R¹⁵)₂,NR¹¹C(═O)NR¹¹(alkylene)-R²⁴, NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B), substitutedalkyl, wherein one of the substituents is a spirocycloalkyl group,optionally substituted (alkylene)_(x)-cycloalkyl, and optionallysubstituted -(alkylene)_(x)-heterocycloalkyl, wherein theheterocycloalkyl does not include unsubstituted N-morpholinyl,N-piperidyl, or N-thiomorpholinyl; wherein any said alkylene group maybe optionally substituted with one to three R¹⁰ groups; provided thatwhen R³, R⁴, R⁵, or R⁶ is C(═O)R¹³, then R¹³ does not include aheterocycloalkyl group that contains a nitrogen bonded to the carbonylmoiety; and the other R³, R⁴, R⁵, or R⁶ moieties can be selectedindependently from H, halogen, R¹⁰, OR²⁰, optionally substituted alkyl,optionally substituted alkenyl, and optionally substituted alkynyl,wherein said optional substituents are one to three R¹⁰ groups; Q isselected from an optionally substituted C₁₋₂ alkylene, wherein saidoptional substituents are one to three R¹⁰ groups; O; S(O)_(y); CH₂-Z′;and Z′-CH₂; wherein Z′ is selected from O and S; R¹⁰ is selected fromalkyl, aryl, heteroaryl, cycloalkyl, spirocycloalkyl, heterocycloalkyl,arylalkoxy, F, Cl, Br, I, CN, CF₃, NR^(31A)R^(31B), NO₂, OR³⁰, OCF₃, ═O,═NR³⁰, ═N—OR³⁰, ═N—NR^(31A)R^(31B), OC(═O)R³⁰, OC(═O)NHR²⁹, O—Si(R²⁹)₄,O-tetrahydropyranyl, ethylene oxide, NR²⁹C(═O)R³⁰, NR²⁹CO₂R³⁰,NR²⁹C(═O)NR^(31A)R^(31B), NHC(═NH)NH₂, NR²⁹S(O)₂R³⁰, S(O)_(y)R¹⁸,CO₂R³⁰, C(═O)NR^(31A)R^(31B), C(═O)R³⁰, (CH₂)_(p)OR³⁰,CH═NNR^(31A)R^(31B), CH═NOR³⁰, CH═NR³⁰, CH═NNHCH(N═NH)NH₂,S(═O)₂NR^(31A)R^(31B), P(═O)(OR³⁰)₂, OR²⁸, and a monosaccharide whereineach hydroxyl group of the monosaccharide is independently eitherunsubstituted or is replaced by H, alkyl, alkylcarbonyloxy, or alkoxy;R¹¹ is selected from H and optionally substituted alkyl, wherein saidoptional substituents are one to three R¹⁰ groups; R¹² is selected fromoptionally substituted alkyl, optionally substituted aryl, andoptionally substituted heteroaryl, wherein said optional substituentsare one to three R¹⁰ groups; R¹³ is independently selected fromoptionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl, wherein said optional substituents are one to threeR¹⁰ groups; R^(14A) and R^(14B) are each independently selected from H,optionally substituted alkyl, optionally substituted aryl, andoptionally substituted heteroaryl, wherein said optional substituentsare one to three R¹⁰ groups; R¹⁵ is independently selected fromoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein said optionalsubstituents are one to three R¹⁰ groups; R^(16A) and R^(16B) are eachindependently selected from H and an optionally substituted alkyl, ortogether with the nitrogen to which they are attached form an optionallysubstituted heterocycloalkyl, wherein said optional substituents are oneto three R¹⁰ groups; R¹⁷ is selected from optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, and optionallysubstituted heteroaryl, wherein said optional substituents are one tothree R¹⁰ groups; R¹⁸ is selected from H, optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl, wherein said optional substituents are one to threeR¹⁰ groups; R¹⁹ is selected from CN and triazole; R²⁰ is selected fromH, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl,wherein said optional substituents are one to three R¹⁰ groups; R²¹ isselected from optionally substituted aryl, and optionally substitutedheteroaryl, wherein said optional substituents are one to three R¹⁰groups; R²² is optionally substituted C₅–C₁₀ alkyl, wherein saidoptional substituents are one to three R¹⁰ groups; R²³ is selected fromoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl, wherein said optional substituents are one to threeR¹⁰ groups; R²⁴ is selected from optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, OR²⁰, O(CH₂)_(p)OR²⁰, (CH₂)_(p)OR²⁰, SR¹⁷,SOR¹⁵, SO₂R¹⁸, CN, N(R¹⁸)₂, C(═O)N(R¹⁸)₂, NR¹⁸C(═O)R¹⁸,NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸, C(R¹²)═NOR¹⁸, NHOR²⁰,NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸, OCOR¹⁵, OC(═O)N(R¹⁸)₂,NR¹⁸C(═O)OR¹⁵, and C(═O)R¹⁸, wherein said optional substituents are oneto three R¹⁰ groups; R²⁵ is selected from optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, OR²⁰,O(CH₂)_(p)OR²⁰, (CH₂)_(p)OR²⁰, SR¹⁷, SOR¹⁵, SO₂R²⁰, CN, N(R¹⁷)₂,C(═O)N(R¹⁸)₂, NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸,C(R¹²)═NOR¹⁸, NHOR²⁰, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸,OCOR¹⁵, OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁵, and C(═O)R¹⁸, wherein saidoptional substituents are one to three R¹⁰ groups; R²⁶ is selected fromoptionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, OR¹¹, O(CH₂)_(p)OR²⁰, (CH₂)_(p)OR²⁰, SR¹⁷, SOR¹⁵, SO₂R¹⁸,CN, N(R¹⁸)₂, C(═O)N(R¹⁸)₂, NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸,C(R¹²)═NOR¹⁸, NHOR²⁰, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸,OCOR¹⁵, OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁵, and C (═O)R¹⁸, wherein saidoptional substituents are one to three R¹⁰ groups; R²⁷ is selected fromoptionally substituted cycloalkyl, CN, C(R¹²)═NOR¹⁸, and C(═O)N(R¹⁸)₂,wherein said optional substituents are one to three R¹⁰ groups; R²⁸ isthe residue of an amino acid after the removal of the hydroxylmoietyfrom the carboxyl group thereof; R²⁹ is H or alkyl; R³⁰ is H,alkyl, aryl, arylalkyl, heteroaryl, cycloalkyl, or heterocycloalkyl;R^(31A) and R^(31B) are each independently selected from H, alkyl, andarylalkyl, or together with the nitrogen to which they are attached forma heterocycloalkyl; R³² is optionally substituted aryl, wherein saidoptional substituents are one to three R¹⁰ groups; R³³ is selected fromoptionally substituted cycloalkyl, optionally substituted heteroaryl,and optionally substituted heterocycloalkyl, wherein said optionalsubstituents are one to three R¹⁰ groups; p is independently selectedfrom 1, 2, 3, and 4; x is 0 or 1; and y is independently selected from0, 1 and 2; or a stereoisomer or pharmaceutically acceptable salt formthereof.
 2. The compound of claim 1 wherein A¹, A² are H, H.
 3. Thecompound of claim 1 wherein R³ is selected from the group consisting ofOR¹³, NR¹¹R³², NR¹¹R³³, (alkylene)-NR¹⁸R¹⁹, C(R¹²)═N—R¹⁸, CH═N—OR¹³,C(R¹²)═N—OR²⁰, OC(═O)NR¹¹(alkylene)-R²⁶, NR¹¹C(═O)NR¹¹R²³,NR¹¹C(═S)NR¹¹R²³, NR¹¹C(═O)NR¹¹(alkylene)-R²⁴,NR¹¹C(═O)N(R¹¹)NR^(16A)R^(16B), C(═O)-cycloalkyl, and optionallysubstituted -(alkylene)_(x)-heterocycloalkyl.
 4. The compound of claim 1wherein ring B together with the carbon atoms to which it is attached,is a 5-membered aromatic ring in which from 1 to 2 carbon atoms may bereplaced by nitrogen atoms; and Q is selected from an optionallysubstituted C₁₋₂ alkylene, wherein said optional substituents are one tothree R¹⁰ groups.
 5. The compound of claim 4 wherein the B ring is apyrazolylene.
 6. The compound of claim 4 having a structure of FormulaIII:

wherein ring B is a pyrazolylene, and R¹ is H or unsubstituted alkyl. 7.The compound of claim 6 having a structure of Formula V:


8. The compound of claim 6 having Formula VI:


9. The compound of claim 6 wherein at least one of R³, R⁴, R⁵, or R⁶ isNR¹¹R³².
 10. The compound of claim 7 wherein at least one of R³, R⁴, R⁵,or R⁶ is NR¹¹R³².
 11. The compound of claim 6 wherein at least one ofR³, R⁴, R⁵, or R⁶ is optionally substituted-(alkylene)_(x)-heterocycloalkyl, wherein the heterocycloalkyl does notinclude unsubstituted N-morpholinyl, N-piperidyl, or N-thiomorpholinyl.12. The compound of claim 11 wherein at least one of R³, R⁴, R⁵, or R⁶is tetrahydropyranyl.
 13. The compound of claim 6 wherein at least oneof R³, R⁴, R⁵, or R⁶ is NR¹¹R³³.
 14. The compound of claim 7 wherein atleast one of R³, R⁴, R⁵, or R⁶ is NR¹¹R³³.
 15. The compound of claim 13wherein R³³ is optionally substituted heteroaryl.
 16. The compound ofclaim 14 wherein R³³ is optionally substituted heteroaryl.
 17. Thecompound of claim 1 wherein the compound is


18. The compound of claim 1 wherein the compound is


19. A pharmaceutical composition comprising a compound of claim 1 and atleast one pharmaceutically acceptable excipient.
 20. The pharmaceuticalcomposition of claim 19, wherein the compound is


21. The pharmaceutical composition of claim 19, wherein the compound is